FIELD OF THE INVENTION
[0001] The present invention relates to substituted heterocyclic compounds, and compositions
thereof as well as such compounds and compositions for use as hypoxia mimetics. This
invention further discloses methods of increasing HIF (Hypoxia Inducible Factor) levels
or activity in a subject or treating a condition associated with HIF levels or activity
such as ischemia, anemia, wound healing, auto-transplantation, allo-transplantation,
xenotransplantation, systemic high blood pressure, thalassemia, diabetes, cancer,
and an inflammatory disorder.
BACKGROUND OF THE INVENTION
[0002] The cellular transcription factor HIF (Hypoxia Inducible Factor) occupies a central
position in oxygen homeostasis in a wide range of organisms and is a key regulator
of responses to hypoxia. The genes regulated by HIF transcriptional activity can play
critical roles in angiogenesis, erythropoiesis, hemoglobin F production, energy metabolism,
inflammation, vasomotor function, apoptosis and cellular proliferation. HIF can also
play a role in cancer, in which it is commonly upregulated, and in the pathophysiological
responses to ischemia and hypoxia.
[0003] The HIF transcriptional complex comprises an heterodimer: HIF is a constitutive nuclear
protein that dimerizes with oxygen-regulated HIF subunits. Oxygen regulation occurs
through hydroxylation of the HIF subunits, which are then rapidly destroyed by the
proteasome. In oxygenated cells, the von Hippel-Lindau tumor suppressor protein (pVHL)
binds to hydroxylated HIF-subunits, thereby promoting their ubiquitin dependent proteolysis.
This process is suppressed under hypoxic conditions, stabilizing HIF and promoting
transcriptional activation by the HIF complex.
[0004] Hydroxylation of HIF-subunits can occur on proline and asparagine residues and can
be mediated by a family of 2-oxoglutarate dependent enzymes. This family includes
the HIF prolyl hydroxylase isozymes (PHDs), which hydroxylate Pro 402 and Pro 564
of human HIF1, as well as Factor Inhibiting HIF (FIH), which hydroxylates Asn 803
of human HIF1. Inhibition of FIH or the PHDs leads to HIF stabilization and transcriptional
activation. See,
e.g., Schofield and Ratcliffe, Nature Rev. Mol. Cell Biol., Vol5, pages 343-354 (2004).
[0005] WO 2007/103905 describes bicyclic heteroaromatic N-substituted glycine derivatives, which are described
to be antagonists of HIF prolyl hydroxylases and are described to be useful for treating
diseases benefiting from the inhibition of this enzyme, anemia being one example.
[0006] WO 2007/025169 describes HIF-1 inhibitors and methods of use thereof.
[0007] Thus, new or improved agents that modulate (such as increasing HIF levels or activity)
HIF are continually needed for developing new and more effective pharmaceuticals to
treat HIF-associated conditions or diseases or disorders, such as ischemia, anemia,
wound healing, auto-transplantation, allo-transplantation, xenotransplantation, systemic
high blood pressure, thalassemia, diabetes, cancer, and an inflammatory disorder,
to name a few. In discovering new or improved agents that modulate HIF level or activity,
it is also desirable but not required to discover agents with improved chemical or
biological properties such as solubility, bioavailability, pharmacokinetics, pharmacodynamics,
toxicity and/or less side effects such as less cardiovascular side effects. The compounds,
compositions, and methods described herein are directed toward these needs and other
ends.
SUMMARY OF THE INVENTION
[0008] The present invention provides,
inter alia, compounds of Formula I:
or a pharmaceutically acceptable salt thereof, a solvate thereof or a chelate thereof
as defined in claim 1.
[0009] The present invention further provides pharmaceutical compositions as defined in
claim 58. The present invention further provides use of the compounds of Formula I
in the manufacture of a medicament for the treatment of a disease, disorder, or condition
as defined in claim 62.
[0010] Further embodiments are set forth in the appended dependent claims.
DESCRIPTION OF DRAWINGS
[0011]
Figure 1 illustrates certain example compounds' effects on the level of EPO in mice
4 hours after the administration of different compounds (using the assay described
in Example B).
Figure 2 illustrates certain example compounds' effects on the level of red blood
cell counts (RBC) in mice at Day 9 after 7 days of daily dosage of 60 mg/kg (using
the assay described in Example C).
Figure 3 illustrates certain example compounds' effects on the level of blood hemoglobin
(HGB) in mice at Day 9 after 7 days of daily dosage of 60 mg/kg (using the assay described
in Example C).
Figure 4 illustrates the pharmacokinetic curves in rats for certain example compounds
after single oral dosage of 50 mg/kg (using the assay described in Example D).
DETAILED DESCRIPTION
[0012] The present invention provides,
inter alia, compounds of Formula I:
or a pharmaceutically acceptable salt thereof, a solvate thereof, or a chelate thereof,
wherein:
n is 1 to 6;
R1 is OH, SH, NR3R4, NHC(O)R2, NHSO2R2 or sulfonyl;
R2 is H, C1-C6 alkyl or substituted C1-C6 alkyl;
R3 and R4 are each independently H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 haloalkyl, substituted C1-C6 haloalkyl; or at least one pair of R3 and R4, together with the same carbon atom to which they are attached, may join to form
a 3 to 6 membered ring or a substituted 3 to 6 membered ring;
R5 is OH, SH, NH2, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, or sulfanyl;
each of R6 and R7 is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, NR3R4, C(O)OH, OR12, SR12, SO2R12, CN, NO2, halo, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted heteroarylalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylsilyl,
substituted alkylsilyl, alkynylsilyl, substituted alkynylsilyl, alkoxy, substituted
alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, or -X-R11;
or R6 and R7, together with the carbon atoms to which they are attached, join to form a 4 to 7
membered ring or a substituted 4 to 7 membered ring;
X is -N(R10)-Y- or -Y-N(R10)-;
Y is C(O), SO2, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene,
or substituted alkynylene;
R8 is H, heteroaryl, substituted heteroaryl, phenyl, or phenyl substituted by halogen,
alkyl, alkoxy, haloalkyl, or haloalkoxy, wherein at least one of R8 and R9 is phenyl substituted with halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy at the
para- or meta- position; or wherein one of R8 and R9 is phenyl substituted with halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy at the
para- or meta- position; and the other of R8 and R9 is H, halogen, OH, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy;
or wherein one of R8 and R9 is phenyl substituted with halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy at the
para- or meta- position; and the other of R8 and R9 is H;
R10 is H, C1-C6 alkyl, or substituted C1-C6 alkyl;
R11 is H, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl,
or substituted heteroaryl; and
R12 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl or NR3R4;
wherein substituted refers to a group in which one or more hydrogen atoms are each
independently replaced with the same or different substituent(s) wherein substituents
include -X, -R33, -OH, =O, -OR33, SR33, -SH, =S, -NR33R34, =NR33, -CX3, -CF3, -CN, -NO2, -S(O)2R33, -OS(O2)OH, -OS(O)2R33, -OP(O)(OR33)(OR34), -C(O)R33, -C(S)R33, -C(O)OR33, -C(O)NR33R34, -C(O)OH, -C(S)OR33, -NR35C(O)NR33R34, -NR35C(S)NR33R34, -NR35C(NR33)NR33R34, -C(NR33)NR33R34, -S(O)2NR33R34, -NR35S(O)2R33, -NR35C(O)R33, and S(O)R33 where each X is independently a halo; each R33 and R34 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted
heterocycloalkyl, heteroaryl , substituted heteroaryl, heteroarylalkyl, substituted
heteroarylalkyl, -NR35R36, -C(O)R35 or -S(O)2R35 or optionally R33 and R34 together with the atom to which R33 and R34 are attached form one or more heterocycloalkyl, substituted heterocycloalkyl, heteroaryl,
or substituted heteroaryl rings; and R35 and R36 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted
heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, or optionally R35 and R36 together with the nitrogen atom to which R35 and R36 are attached form one or more heterocycloalkyl, substituted heterocycloalkyl, heteroaryl,
or substituted heteroaryl rings.
[0013] In some embodiments, R
1 is OH or SH.
[0014] In some further embodiments, R
1 is OH.
[0015] In some embodiments, R
2 is H or C
1-C
6 alkyl (such as methyl or ethyl).
[0016] In some further embodiments, R
2 is H.
[0017] In some embodiments, R
3 and R
4 are each independently H, C
1-C
6 alkyl, or C
1-C
6 haloalkyl.
[0018] In some embodiments, R
3 and R
4 are each independently H or C
1-C
6 alkyl (such as methyl or ethyl).
[0019] In some embodiments, R
3 and R
4 are each H.
[0020] In some embodiments, R
5 is OH, SH, NH
2, or C
1-C
6 alkoxy.
[0021] In some further embodiments, R
5 is OH.
[0022] In some embodiments, at least one of R
6 and R
7 is halo or a moiety substituted with at least one halo.
[0023] In some embodiments, at least one of R
6 and R
7 is independently alkoxy or substituted alkoxy..
[0024] In some embodiments, at least one of R
6 and R
7 is independently aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl,
or substituted heterocycloalkyl.
[0025] In some embodiments, R
8 is substituted phenyl or substituted heteroaryl.
[0026] In some embodiments, one of R
8 and R
9 is substituted phenyl, or R
8 is substituted pyridyl.
[0027] In some embodiments, one of R
8 and R
9 is phenyl or phenyl substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy
at the para- and/or meta- position.
[0028] In some embodiments, R
8 is pyridyl or pyridyl substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy
at the para- and/or meta- position.
[0029] In some embodiments, the compound of Formula I is a compound of Formula II:
wherein:
R21 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R22 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
Z1 is CR23; and R23 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
provided that at least one of R21 and R22 and R23, if present, is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
[0030] In some embodiments of compound of Formula II, R
21 is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
[0031] In some embodiments of compound of Formula II, R
22 is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
[0032] In some embodiments of compound of Formula II, R
23 is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
[0033] In some embodiments of compound of Formula II, one of R
21, R
22, and R
23 is halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy; and the other two of R
21, R
22, and R
23 are each H.
[0034] In some embodiments of compound of Formula II, one of R
21 and R
23 is halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy; and the other one of R
21 and R
23 is H.
[0035] In some further embodiments of compound of Formula II, R
22 is H.
[0036] In some embodiments of compound of Formula II, two of R
21, R
22, and R
23 are each independently halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy; and the other one of R
21, R
22, and R
23 is H.
[0037] In other further embodiments of compound of Formula II, R
22 is H.
[0038] In some embodiments of compound of Formula II, R
21, R
22, and R
23 are each independently halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy.
[0039] In some embodiments of compound of Formula II one of R
21 and R
22 is halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy; and the other of R
21 and R
22 is H.
[0040] In some embodiments, the compound of Formula II is a compound of Formula IIa:
wherein:
R21 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; and
R22 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
provided that at least one of R21 and R22 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
[0041] In some embodiments of compound of Formula IIa, R
21 is H; and R
22 is halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy.
[0042] In some embodiments of compound of Formula IIa, R
21 is H; and R
22 is C
1-C
6 alkyl or C
1-C
6 haloalkyl.
[0043] In some embodiments of compound of Formula IIa, R
22 is methyl or C
1-C
2 haloalkyl.
[0044] In some embodiments of compound of Formula IIa, R
22 is methyl or ethyl.
[0045] In some embodiments of compound of Formula IIa, R
22 is H; and R
21 is halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy.
[0046] In some embodiments of compound of Formula IIa, R
22 is H; and R
21 is C
1-C
6 alkyl or C
1-C
6 haloalkyl.
[0047] In some embodiments of compound of Formula IIa, R
21 is methyl or C
1-2 haloalkyl.
[0048] In some embodiments of compound of Formula IIa, R
21 is methyl or ethyl.
[0049] In some embodiments of compound of Formula IIa, R
21 and R
22 are each independently halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy.
[0050] In some embodiments of compound of Formula IIa, R
21 and R
22 are each independently C
1-C
2 alkyl or C
1-C
2 haloalkyl.
[0051] In some embodiments, the compound of Formula I is a compound of Formula III:
wherein:
R24 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R25 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6r haloalkoxy;
Z2 is N or CR26; and R26 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
provided that at least one of R24 and R25 and R26 , if present, is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
[0052] In some embodiments of compound of formula III, Z
2 is CR
26.
[0053] In some embodiments of compound of Formula III, R
24 is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
[0054] In some embodiments of compound of Formula III, R
25 is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
[0055] In some embodiments of compound of Formula III, Z
2 is CR
26 and R
26 is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
[0056] In some embodiments of compound of Formula III, Z
2 is CR
26; one of R
24, R
25, and R
26 is halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy; and the other two of R
24, R
25, and R
26 are each H.
[0057] In some embodiments of compound of Formula III, Z
2 is CR
26; one of R
24 and R
26 is halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy; and the other one of R
24 and R
26 is H.
[0058] In some embodiments of compound of Formula III, Z
2 is CR
26; two of R
24, R
25, and R
26 are each independently halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy; and the other one of R
24, R
25, and R
26 is H.
[0059] In some embodiments of compound of Formula III, Z
2 is CR
26; R
24, R
25, and R
26 are each independently halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy.
[0060] In some embodiments of compound of Formula III, Z
2 is N.
[0061] In some embodiments of compound of Formula III, one of R
24 and R
25 is halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy,or C
1-C
6 haloalkoxy; and the other of R
24 and R
25 is H.
[0062] In some embodiments, the compound of Formula III is a compound of Formula IIIa
wherein:
R24 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; and
R25 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
provided that at least one of R24 and R25 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
[0063] In some embodiments of compound of Formula IIIa, R
24 is H; and R
25 is halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy.
[0064] In some embodiments of compound of Formula IIIa, R
25 is methyl or C
1-C
2 haloalkyl.
[0065] In some embodiments of compound of Formula IIIa, R
25 is H; and R
24 is halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy.
[0066] In some embodiments of compound of Formula IIIa, R
24 is methyl or C
1-C
2 haloalkyl.
[0067] In some embodiments of compound of Formula IIIa, R
24 and R
25 are each independently halogen, C
1-C
6 alkyl, C
1-C
6 haloalkyl, C
1-C
6 alkoxy, or C
1-C
6 haloalkoxy.
[0068] In some embodiments of compound of Formula I, wherein the compound is:
2-(4-hydroxy-2-oxo-7-phenyl-2H-chromene-3-carboxamido)acetic acid;
2-(7-(2-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(7-(3-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(7-(4-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-7-(4-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-7-(3-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-7-(4-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(7-(3,4-dichlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(7-(3,4-difluorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-(3,4,5-trifluorophenyl)-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-7-(3-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-7-(4-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-m-tolyl-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-p-tolyl-2H-chromene-3-carboxamido)acetic acid;
2-(8-(2-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(8-(3-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(8-(4-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-8-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-8-(4-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-8-(3-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-8-(4-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(8-(3,4-dichlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(8-(3,4-difluorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-8-(3,4,5-trifluorophenyl)-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-8-(3-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-8-(4-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-8-m-tolyl-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-8-p-tolyl-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-7-(6-methoxypyridin-3-yl)-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-(pyridin-4-yl)-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-(pyridin-3-yl)-2H-chromene-3-carboxamido)acetic acid; or
2-(4-hydroxy-2-oxo-8-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic
acid.
[0069] Also provided herein is a pharmaceutical composition comprising at least one pharmaceutically
acceptable excipient, adjuvant, or carrier, and a therapeutically effective amount
of at least one compound described herein.
[0070] Further provided are pharmaceutical compositions comprising at least one pharmaceutically
acceptable excipient, adjuvant, or carrier, and a therapeutically effective amount
of at least one compound described herein.
[0071] In some embodiments, the pharmaceutical compositions comprise at least one additional
compound such as an erythropoiesis stimulating agent or chemotherapeutic agent.
[0072] Additionally provided herein is the pharmaceutical compositions with at least one
compound described herein or pharmaceutically acceptable salt thereof in an amount
effective for the treatment of ischemia, anemia, wound healing, auto-transplantation,
allo-transplantation, xeno-transplantation, systemic high blood pressure, thalassemia,
diabetes, cancer, an inflammatory disorder, or a combination thereof.
[0073] Further provided is the pharmaceutical compositions with at least one compound described
herein or pharmaceutically acceptable salt thereof in an amount effective for the
treatment of a disease, a disorder, a condition associated with the HIF level or HIF
activity.
[0074] Also provided is a use of a compound described herein or pharmaceutically acceptable
salt thereof in the manufacturing a medicament for, treating an anemic or ischemic
related disorder in a subject comprising administering to a subject at least one compound
described herein.
[0075] Also provided is a use of a compound described herein or pharmaceutically acceptable
salt thereof in the manufacturing a medicament for, treating ischemia, anemia, wound
healing, auto-transplantation, allo-transplantation, xeno-transplantation, systemic
high blood pressure, thalassemia, diabetes, cancer, an inflammatory disorder, or a
combination of two or more thereof in a subject comprising administering to a subject
at least one compound described herein.
[0076] Also provided is a use of a compound described herein or pharmaceutically acceptable
salt thereof in the manufacturing a medicament for, treating anemia in a subject comprising
administering to a subject at least one compound described herein.
[0077] Also provided is a use of a compound described herein or pharmaceutically acceptable
salt thereof in the manufacturing a medicament for, modulating angiogenesis in a subject
comprising administering to the subject at least one compound described herein.
[0078] Additionally provided is a use of a compound described herein or pharmaceutically
acceptable salt thereof in the manufacturing a medicament for, treating at least one
disease in a patient in need of such treatment comprising administering to the patient
a therapeutically effective amount of at least one compound described herein.
[0079] Also provided is a use of a compound described herein or pharmaceutically acceptable
salt thereof in the manufacturing a medicament for, inhibiting HIF hydroxylation in
a subject comprising administering to the subject at least one compound described
herein.
[0080] Additional embodiments of the invention are set forth in the description which follows,
or may be learned by practice of the invention.
[0081] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction
conditions, and so forth used in the specification and claims are to be understood
as being modified in all instances by the term "about." Accordingly, unless indicated
to the contrary, the numerical parameters set forth in the following specification
and attached claims are approximations that may vary depending upon the standard deviation
found in their respective testing measurements.
[0082] As used herein, when any variable occurs more than one time in a chemical formula,
its definition on each occurrence is independent of its definition at every other
occurrence. The compounds of the present disclosure may contain one or more chiral
centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond
isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, any
chemical structures within the scope of the specification depicted, in whole or in
part, with a relative configuration encompass all possible enantiomers and stereoisomers
of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically
pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric
mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into the component
enantiomers or stereoisomers using separation techniques or chiral synthesis techniques
well known to the skilled artisan.
[0083] Compounds of Formula I, II, IIa, III and IIIa include, but are not limited to optical
isomers of compounds of Formula I, II, IIa, III and IIIa, racemates, and other mixtures
thereof. In those situations, the single enantiomers or diastereomers, i.e., optically
active forms, can be obtained by asymmetric synthesis or by resolution of the racemates.
Resolution of the racemates can be accomplished, for example, by conventional methods
such as crystallization in the presence of a resolving agent, or chromatography, using,
for example a chiral high-pressure liquid chromatography (HPLC) column. In addition,
compounds of Formula I, II, IIa, III and IIIa include Z- and E- forms (or cis- and
trans- forms) of compounds with double bonds. Where compounds of Formula I, II, IIa,
III and IIIa exists in various tautomeric forms, chemical entities of the present
invention include all tautomeric forms of the compound.
[0084] Compounds of the present disclosure include, but are not limited to compounds of
Fomula I and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable
forms of the compounds recited herein include pharmaceutically acceptable salts, solvates,
crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes,
prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein
are in the form of pharmaceutically acceptable salts. As used henceforth, the term
"compound" encompasses not only the compound itself, but also a pharmaceutically acceptable
salt thereof, a solvate thereof, a chelate thereof, and mixtures of any of the foregoing.
[0085] The term "solvate" refers to the compound formed by the interaction of a solvent
and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as
hydrates, including monohydrates and hemi-hydrates.
[0086] At various places in the present specification, substituents of compounds of the
invention are disclosed in groups or in ranges. It is specifically intended that the
invention include each and every individual subcombination of the members of such
groups and ranges. For example, the term "C
1-3 alkyl" is specifically intended to individually disclosed methyl, ethyl, and C
3 alkyl (including n-propryl and isopropyl).
[0087] For compounds of the invention in which a variable appears more than once, each variable
can be a different moiety selected from the Markush group defining the variable. For
example, where a structure is described having two R groups that are simultaneously
present on the same compound; the two R groups can represent different moieties selected
from the Markush group defined for R.
[0088] It is further appreciated that certain features of the invention, which are, for
clarity, described in the context of separate embodiments, can also be provided in
combination in a single embodiment. Conversely, various features of the invention
which are, for brevity, described in the context of a single embodiment, can also
be provided separately or in any suitable subcombination.
[0089] The term "n-membered" where n is an integer typically describes the number of ring-forming
atoms in a moiety where the number of ring-forming atoms is n. For example, pyridine
is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered
heteroaryl group.
[0090] "Alkyl" refers to a saturated, branched or straight-chain monovalent hydrocarbon
group derived by the removal of one hydrogen atom from a single carbon atom of a parent
alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls
such as propan-1-yl, propan-2-yl, and cyclopropan-1-yl, butyls such as butan-1-yl,
butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, tert-butyl,
and the like. In certain embodiments, an alkyl group comprises from 1 to 20 carbon
atoms. As used herein the term "lower alkyl" refers to an alkyl group comprising from
1 to 6 carbon atoms.
[0091] "Alkenyl" refers to an unsaturated branched, straight-chain or cyclic alkyl group
having at least one carbon-carbon double bond derived by the removal of one hydrogen
atom from a single carbon atom of a parent alkene. The group may be in either the
Z- or E- forms (or
cis or
trans conformation) about the double bond(s). Typical alkenyl groups include, but are not
limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl
(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as
but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,
buta- 1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl;and
the like. In certain embodiments, an alkenyl group has from 2 to 20 carbon atoms and
in other embodiments, from 2 to 6 carbon atoms, i.e. "lower alkenyl."
[0092] "Alkynyl" refers to an unsaturated branched or straight-chain having at least one
carbon-carbon triple bond derived by the removal of one hydrogen atom from a single
carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited
to, ethynyl; propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the
like. In certain embodiments, an alkynyl group has from 2 to 20 carbon atoms and in
other embodiments, from 2 to 6 carbon atoms (i.e. "lower alkynyl").
[0093] "Alkoxy" refers to a radical -OR where R represents an alkyl. Representative examples
include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy,
and the like.
[0094] "Alkoxycarbonyl" refers to a radical -C(O)-OR where R represents an alkyl as defined
herein.
[0095] "Aryl" refers to a monovalent aromatic hydrocarbon group derived by the removal of
one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl
encompasses 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic
ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene,
indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic
and aromatic, for example, fluorene. For example, aryl includes 5- and 6-membered
carbocyclic aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring containing
1 or more heteroatoms selected from N, O, and S. In certain embodiments, an aryl group
can comprise from 6 to 10 carbon atoms. Aryl, however, does not encompass or overlap
in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic
aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring
system is heteroaryl, not aryl, as defined herein.
[0096] "Arylalkyl" or "aralkyl" refers to an acyclic alkyl group in which one of the hydrogen
atoms bonded to a carbon atom, typically a terminal or
sp3 carbon atom, is replaced with an aryl group. Typical arylalkyl groups include, but
are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,
2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl
and the like. Where specific alkyl moieties are intended, the nomenclature arylalkyl,
arylalkenyl, and/or arylalkynyl is used. In certain embodiments, an arylalkyl group
can be (C
6-30) arylalkyl, e.g., the alkyl group of the arylalkyl group can be (C
1-10) and the aryl moiety can be (C
5-20).
[0097] "Carbonyl" refers to a radical -C(O) group.
[0098] "Carboxy" refers to the radical -C(O)OH.
[0099] "Cyano" refers to the radical -CN.
[0100] "Cycloalkyl" refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl
group. Where a specific level of saturation is intended, the nomenclature "cycloalkanyl"
or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited
to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and
the like. In certain embodiments, the cycloalkyl group can be C
3-10 cycloalkyl, such as, for example, C
3-6 cycloalkyl.
[0101] "Heterocycloalkyl" refers to a saturated or unsaturated, but non-aromatic, cyclic
alkyl group in which one or more carbon atoms (and any associated hydrogen atoms)
are independently replaced with the same or different heteroatom and its associated
hydrogen atoms, where appropriate. Typical heteroatoms to replace the carbon atom(s)
include, but are not limited to, N, P, O, S, and Si. Where a specific level of saturation
is intended, the nomenclature "heterocycloalkanyl" or "heterocycloalkenyl" is used.
Typical heterocycloalkyl groups include, but are not limited to, groups derived from
epoxides, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine,
quinuclidine, tetrahydrofuran, tetrahydropyran and the like. Substituted heterocycloalkyl
also includes ring systems substituted with one or more oxo (=O) or oxide (-O
-) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl
and 1,1-dioxo-1-thiomorpholinyl.
[0102] "Disease" refers to any disease, disorder, condition, symptom, or indication.
[0103] "Halo" refers to a fluoro, chloro, bromo, or iodo group.
[0104] "Heteroaryl" refers to a monovalent heteroaromatic group derived by the removal of
one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl
encompasses: 5- to 7-membered aromatic, monocyclic rings containing one or more, for
example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected
from N, O, and S, with the remaining ring atoms being carbon; and polycyclic heterocycloalkyl
rings containing one or more, for example, from 1 to 4, or in certain embodiments,
from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms
being carbon and wherein at least one heteroatom is present in an aromatic ring.
[0105] For example, heteroaryl includes a 5- to 7-membered heteroaromatic ring fused to
a 5- to 7-membered cycloalkyl ring and a 5- to 7-membered heteroaromatic ring fused
to a 5- to 7-membered heterocycloalkyl ring. For such fused, bicyclic heteroaryl ring
systems wherein only one of the rings contains one or more heteroatoms, the point
of attachment may be at the heteroaromatic ring or the cycloalkyl ring. When the total
number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not
adjacent to one another. In certain embodiments, the total number of S and O atoms
in the heteroaryl group is not more than 2. In certain embodiments, the total number
of S and O atoms in the aromatic heterocycle is not more than 1. Heteroaryl does not
encompass or overlap with aryl as defined above. Typical heteroaryl groups include,
but are not limited to, groups derived from acridine, arsindole, carbazole, β-carboline,
chromane, chromene, cinnoline, furan, imidazole, indazole, indole,. indoline, indolizine,
isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,
naphthyridine, oxadiazole, oxazole, perirnidine, phenanthridine, phenanthroline, phenazine,
phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,
pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole,
thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In certain embodiments,
the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example,
a 5 to 10 membered heteroaryl. In certain embodiments, heteroaryl groups can be those
derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline,
imidazole, oxazole, and pyrazine.
[0106] "Heteroarylalkyl" or "heteroaralkyl" refers to an acyclic alkyl group in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon
atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended,
the nomenclature heteroarylalkanyl, heteroarylalkenyl, and/or heteroarylalkynyl is
used. In certain embodiments, the heteroarylalkyl group can be a 6 to 30 membered
heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl
can be 1 to 10 membered and the heteroaryl moiety can be a 5 to 20-membered heteroaryl.
[0107] "Sulfonyl" refers to a radical -S(O)
2R where R is an alkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl,
substituted aryl, or substituted heteroaryl group as defined herein. Representative
examples include, but are not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl,
butylsulfonyl, and the like.
[0108] "Sulfanyl" refers to a radical -SR where R is an alkyl, substituted alkyl, substituted
cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl
group as defined herein that may be optionally substituted as defined herein. Representative
examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio,
and the like.
[0109] "Pharmaceutically acceptable" refers to generally recognized for use in animals,
and more particularly in humans.
[0110] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically
acceptable and that possesses the desired pharmacological activity of the parent compound.
Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like;
or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic
acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic
acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)
benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced
by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion;
or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine,
N-methylglucamine, dicyclohexylamine, and the like.
[0111] "Pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," or
"pharmaceutically acceptable adjuvant" refer, respectively, to an excipient, carrier
or adjuvant with which at least one compound of the present disclosure is administered.
[0112] "Pharmaceutically acceptable vehicle" refers to any of a diluent, adjuvant, excipient
or carrier with which at least one compound of the present disclosure is administered.
[0113] "Stereoisomer" refers to an isomer that differs in the arrangement of the constituent
atoms in space. Stereoisomers that are mirror images of each other and optically active
are termed "enantiomers," and stereoisomers that are not mirror images of one another
and are optically active are termed "diastereoisomers."
[0114] "Subject" includes mammals and humans. The terms "human" and "subject" are used interchangeably
herein.
[0115] "Substituted" refers to a group in which one or more hydrogen atoms are each independently
replaced with the same or different substituent(s). Typical substituents include,
but are not limited to, -X, -R
33, -OH, =O, -OR
33, SR
33, -SH, =S, -NR
33R
34, =NR
33, -CX
3, -CF
3, -CN, -NO
2, -S(O)
2R
33, -OS(O
2)OH, -OS(O)
2R
33, -OP(O)(OR
33)(OR
34), -C(O)R
33, -C(S)R
33, -C(O)OR
33, -C(O)NR
33R
34, -C(O)OH, -C(S)OR
33, -NR
35C(O)NR
33R
34, -NR
35C(S)NR
33R
34, -NR
35C(NR
33)NR
33R
34, -C(NR
33)NR
33R
34, -S(O)
2NR
33R
34, -NR
35S(O)
2R
33, -NR
35C(O)R
33, and S(O)R
33 where each X is independently a halo; each R
33 and R
34 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted
heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted
heteroarylalkyl, -NR
35R
36, -C(O)R
35 or -S(O)
2R
35 or optionally R
33 and R
34 together with the atom to which R
33 and R
34 are attached form one or more heterocycloalkyl, substituted heterocycloalkyl, heteroaryl,
or substituted heteroaryl rings; and R
35 and R
36 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted
heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, or optionally R
35 and R
36 together with the nitrogen atom to which R
35 and R
36 are attached form one or more heterocycloalkyl, substituted heterocycloalkyl, heteroaryl,
or substituted heteroaryl rings. In certain embodiments, a tertiary amine or aromatic
nitrogen may be substituted with one or more oxygen atoms to form the corresponding
nitrogen oxide.
[0116] "Therapeutically effective amount" refers to the amount of a compound that, when
administered to a subject for treating a disease, or at least one of the clinical
symptoms of a disease or disorder, is sufficient to affect such treatment for the
disease, disorder, or symptom. The "therapeutically effective amount" can vary depending
on the compound, the disease, disorder, and/or symptoms of the disease or disorder,
severity of the disease, disorder, and/or symptoms of the disease or disorder, the
age of the subject to be treated, and/or the weight of the subject to be treated.
An appropriate amount in any given instance can be readily apparent to those skilled
in the art or capable of determination by routine experimentation.
[0117] "Treating" or "treatment" of any disease or disorder refers to arresting or ameliorating
a disease, disorder, or at least one of the clinical symptoms of a disease or disorder,
reducing the risk of acquiring a disease, disorder, or at least one of the clinical
symptoms of a disease or disorder, reducing the development of a disease, disorder
or at least one of the clinical symptoms of the disease or disorder, or reducing the
risk of developing a disease or disorder or at least one of the clinical symptoms
of a disease or disorder. "Treating" or "treatment" also refers to inhibiting the
disease or disorder, either physically, (e.g., stabilization of a discernible symptom),
physiologically, (e.g., stabilization of a physical parameter), or both, or inhibiting
at least one physical parameter which may not be discernible to the subject. Further,
"treating" or "treatment" refers to delaying the onset of the disease or disorder
or at least symptoms thereof in a subject which may be exposed to or predisposed to
a disease or disorder even though that subject does not yet experience or display
symptoms of the disease or disorder.
[0118] Reference will now be made in detail to embodiments of the present disclosure. While
certain embodiments of the present disclosure will be described, it will be understood
that it is not intended to limit the embodiments of the present disclosure to those
described embodiments. To the contrary, reference to embodiments of the present disclosure
is intended to cover alternatives, modifications, and equivalents as may be included
within the spirit and scope of the embodiments of the present disclosure as defined
by the appended claims.
[0119] Certain embodiments of the present invention are directed to at least one compound
of Formula I:
Or a pharmaceutically acceptable salt thereof, a solvate thereof, or a chelate thereof,
wherein:
n is 1 to 6;
R1 is OH, SH, NR3R4, NHC(O)R2, NHSO2R2 or sulfonyl,;
R2 is H, C1-C6 alkyl or substituted C1-C6 alkyl;
R3 and R4 are each independently H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 haloalkyl, substituted C1-C6 haloalkyl; or at least one pair of R3 and R4, together with the same carbon atom to which they are attached, may join to form
a 3 to 6 membered ring or a substituted 3 to 6 membered ring;
R5 is OH, SH, NH2, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, or sulfanyl;
each of R6 and R7 is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, NR3R4, C(O)OH, OR12, SR12, SO2R12, CN, NO2, halo, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted heteroarylalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylsilyl,
substituted alkylsilyl, alkynylsilyl, substituted alkynylsilyl, alkoxy, substituted
alkoxy,alkoxycarbonyl, substituted alkoxycarbonyl, or -X-R11;
or R6 and R7 together with the carbon atoms to which they are attached join to form a 4 to 7 membered
ring or a substituted 4 to 7 membered ring;
X is -N(R10)-Y- or -Y-N(R10)-;
Y is C(O), SO2, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene,
or substituted alkynylene;
R8 is H, heteroaryl, substituted heteroaryl, phenyl, or phenyl substituted by halogen,
alkyl, alkoxy, haloalkyl, or haloalkoxy, wherein at least one of R8 and R9 is phenyl substituted with halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy at the
para- or meta- position; or wherein one of R8 and R9 is phenyl substituted with halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy at the
para- or meta- position; and the other of R8 and R9 is H, halogen, OH, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy;
or wherein one of R8 and R9 is phenyl substituted with halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy at the
para- or meta- position; and the other of R8 and R9 is H;
R10 is H, C1-C6 alkyl, or substituted C1-C6 alkyl;
R11 is H, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl,
or substituted heteroaryl; and
R12 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl or NR3R4; wherein substituted refers to a group in which one or more hydrogen atoms are each
independently replaced with the same or different substituent(s) wherein substituents
include -X, -R33, -OH, =O, -OR33, SR33, -SH, =S, -NR33R34, =NR33, -CX3, -CF3, -CN, -NO2, -S(O)2R33, -OS(O2)OH, -OS(O)2R33, -OP(O)(OR33)(OR34), -C(O)R33, -C(S)R33, -C(O)OR33, -C(O)NR33R34, -C(O)OH, -C(S)OR33, -NR35C(O)NR33R34, -NR35C(S)NR33R34, -NR35C(NR33)NR33R34, -C(NR33)NR33R34, -S(O)2NR33R34, -NR35S(O)2R33, -NR35C(O)R33, and S(O)R33 where each X is independently a halo; each R33 and R34 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted
heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted
heteroarylalkyl, -NR35R36, -C(O)R35 or -S(O)2R35 or optionally R33 and R34 together with the atom to which R33 and R34 are attached form one or more heterocycloalkyl, substituted heterocycloalkyl, heteroaryl,
or substituted heteroaryl rings; and R35 and R36 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted
heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, or optionally R35 and R36 together with the nitrogen atom to which R35 and R36 are attached form one or more heterocycloalkyl, substituted heterocycloalkyl, heteroaryl,
or substituted heteroaryl rings.
[0120] In certain embodiments of compounds of Formula I, R
1 is OH or SH.
[0121] In certain embodiments of compounds of Formula I, R
2 is H.
[0122] In certain embodiments of compounds of Formula I, R
3 and R
4 are each independently H, C
1-C
6 alkyl such as methyl or ethyl, and substituted C
1-C
6 alkyl (such as C
1-C
6 alkyl substituted with hydroxyl, for example hydroxymethyl).
[0123] In certain embodiments of compounds of Formula I, R
3 and R
4 are each H.
[0124] In certain embodiments of compounds of Formula I, R
5 is OH, SH, NH
2, or C
1-C
6 alkoxy, such as methoxy, ethoxy and propoxy, and a substituted C
1-C
6 alkoxy.
[0125] In certain embodiments of compounds of Formula I, R
3 and R
4 join together to form a 3 to 6 membered ring or a substituted 3 to 6 membered ring.
The 3 to 6 membered rings can comprise at least one heteroatom, such as at least two
heteroatoms.
[0126] In certain embodiments of compounds of Formula I, R
6 and R
7 can join together to form a 4 to 7 membered ring or a substituted 4 to 7 membered
ring. The 4 to 7 membered rings can comprise at least one heteroatom, such as at least
two heteroatoms, and at least three heteroatoms.
[0127] In certain embodiments of compounds of Formula I, at least one of R
6 and R
7 is independently halo and a moiety substituted with at least one halogen, such as
trifluoromethyl.
[0128] In certain embodiments of compounds of Formula I, at least one of R
6 and R
7 is independently alkoxy or substituted alkoxy.
[0129] In certain embodiments of compounds of Formula I, at least one of R
6 and R
7 is independently aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl,
or substituted heterocycloalkyl, such as substituted pyridines, substituted pyrimidines,
substituted pyrazines, substituted pyridazines, substituted tetrahydrofurans, and
substituted piperidines.
[0130] Examples of individual representative compounds of the present disclosure, and compounds
comprised in compositions of the present disclosure, and used in methods of the present
disclosure are listed in Table 1. Each compound listed in Table 1, i.e., Examples
1-38, contains information directed to its structure, name, molecular weight, hydrogen
NMR data and at least one method of synthesis.
[0131] In certain embodiments, compounds of the present disclosure inhibit prolyl hydroxylases
such as HIF prolyl hydroxylases. Variety of assays may be used to determine the prolyl
hydroxylase inhibitory activity of a compound.
[0132] In certain embodiments, compounds of the present disclosure modulate HIF levels or
activity, for example, by stabilizing HIF.
[0133] Furthermore, compounds of the present disclosure can contain one or more chiral centers.
Such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual
enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers,
and enriched mixtures thereof, are included within the scope of the present disclosure.
Pure stereoisomers, and enriched mixtures thereof, can be prepared using, for example,
optically active starting materials or stereoselective reagents well-known in the
art. Alternatively, racemic mixtures of such compounds can be separated using, for
example, chiral column chromatography, chiral resolving agents and the like.
[0134] Certain embodiments of the present disclosure are directed to a pharmaceutical composition
comprising at least one pharmaceutically acceptable excipient, adjuvant or carrier,
and a therapeutically effective amount of at least one compound described herein.
The at least one compound can be present in an amount effective for the treatment
of at least one disease selected from ischemia, anemia, wound healing, auto-transplantation,
allo-transplantation, xeno-transplantation, systemic high blood pressure, thalassemia,
diabetes, cancer and an inflammatory disorder.
Synthesis
[0135] Compounds of the invention, including salts thereof, can be prepared using known
organic synthesis techniques and can be synthesized according to any of numerous possible
synthetic routes.
[0136] The reactions for preparing compounds of the invention can be carried out in suitable
solvents which can be readily selected by one of skill in the art of organic synthesis.
Suitable solvents can be substantially non-reactive with the starting materials (reactants),
the intermediates, or products at the temperatures at which the reactions are carried
out, e.g., temperatures which can range from the solvent's freezing temperature to
the solvent's boiling temperature. A given reaction can be carried out in one solvent
or a mixture of more than one solvent. Depending on the particular reaction step,
suitable solvents for a particular reaction step can be selected by the skilled artisan.
[0137] Preparation of compounds of the invention can involve the protection and deprotection
of various chemical groups. The need for protection and deprotection, and the selection
of appropriate protecting groups, can be readily determined by one skilled in the
art. The chemistry of protecting groups can be found, for example, in
T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley
& Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
[0138] Reactions can be monitored according to any suitable method known in the art. For
example, product formation can be monitored by spectroscopic means, such as nuclear
magnetic resonance spectroscopy (e.g.,
1H or
13C), infrared spectroscopy, spectrophotometry (
e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance
liquid chromatography (HPLC) or thin layer chromatography (TLC).
Examples
[0140] The present invention is further exemplified, but not limited, by the following examples
that illustrate the preparation of compounds of Formulas I, II, IIa, III, or IIIa,
according to the invention.
Example 1
Synthesis of N-[(4-hydroxy-2-oxo-7-phenyl-2H-3-chromenyl)carbonyl]glycine
[0141]
[0142] Reagent
1 (42 g, 33.6 mmol) was dissolved in 200 mL of AC
2O with addition of 1 mL of H
3PO
4, and was heated at 50°C. After its completion, the reaction mixture was cooled to
room temperature, and 500 mL of water was then added in and stirred at 50°C until
hydrolyzation is complete. The reaction mixture was then cooled to 0 °C and filtered.
The resulting solid, Compound
2, was further dried (47 g).
[0143] Compound
2 (25.9 g, 100 mmol) and 1-Hydroxybenzotriazole anhydrous (HOBt, 13.5 g) was dissolved
in 400 mL of THF. Dicyclohexylcarbodiimide (DCC, 20.9 g) was gradually added in at
0 °C and stirred over night at a temperature below 10°C. The reaction mixture was
filtered and the Filtrate A was collected. 13.2 g (100 mmol) of dimethyl malonate
was dissolved in 800 mL of THF first, then 7.2 g sodium hydride (70% dispersion) was
added in. Filtrate A was added while stirred and left to react for 2 hours at room
temperature. After THF removed by vacuum distillation, 400 mL of methanol and 400
mL of 10% HCl were added and stirred over night. After filtration, the resulting solid
was washed with 400 mL of methanol and dried, yielding 14 g of Compound
3.
[0144] Glycine t-butyl ester HCl salt (13.4 g) and sodium methoxide (4.4 g) were suspended
in 200mL of methanol. After stirred to a homogeneous suspension, it was distilled
to remove all methanol. 200 mL of THF and Compound
3 (6.0 g) were added in and the reaction was run at 60°C over night. THF was then removed
by vacuum distillation and 400 mL of methanol was added and stirred for 2 hours. After
filtration and drying, it gave 4.5 g of Compound
4.
[0145] Compound
4 (240 mg, 0.6 mmol), Pd(PPh
3)
4 (140 mg, 0.12 mmol) and phenyl boronic acid (85.4 mg, 0.7 mmol) were dissolved in
1 mL of 2M Na
2CO
3 aqueous solution and 4 mL of DMF. The resulting solution was heated to 80°C under
nitrogen gas overnight. After its completion, the reaction mixture was cooled to room
temperature. 100L of water and 100mL of ethyl acetate were added and stirred. The
organic layer was retained and washed twice more by water, followed by quickly passing
through a silicon gel column to remove solvent. 5mL of dichloromethane and 5mL of
trifluoroacetic acid were then added and stirred at room temperature for 4 hrs. After
its completion, the reaction mixture was evaporated
in vacuo. The resulting product was further purified by recrystallization using CH
3OH-THF to arrive at the title compound
6, with the LC-MS [M-H]
- m/z 338, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 13.01 (br s, 1H), 9.55 (br s, 1H), 8.05 (d, 1H, J = 9.0 Hz), 7.85 (d, 1H, J
= 9.0 Hz), 7.83 (t, 1H, J =7.5 Hz), 7.82 (dd, 2H, J = 7.5, 7.5 Hz), 7.54 (dd, 2H,
J = 7.5, 1.5 Hz), 7.46 (s, 1H), 4.14 (d, 2H, J = 6.0 Hz).
Example 2
Synthesis of N-[(4-hydroxy-2-oxo-7-(2-chloro-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0146]
[0147] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 373, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 13.05 (br s, 1H), 9.57 (br s, 1H), 8.08 (d, 1H, J = 8.4 Hz), 7.66-7.32 (m, 6H),
4.15 (d, 2H, J = 6.0 Hz).
Example 3
Synthesis of N-[(4-hydroxy-2-oxo-7-(3-chloro-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0148]
[0149] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 373, and
1H-NMR (300 MHz, (CD
3)
2SO)δ 13.05 (br s, 1H), 9.55 (br s, 1H), 8.04 (d, 1H, J = 8.4 Hz), 7.92-7.81 (m, 4H),
7.59-7.55 (m, 2H), 4.14 (d, 2H, J = 6.0 Hz).
Example 4
Synthesis of N-[(4-hydroxy-2-oxo-7-(4-chloro-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0150]
[0151] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 373, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.55 (br s, 1H), 8.05 (d, 1H, J = 8.4 Hz), 7.88 (d, 2H, J = 8.7 Hz), 7.84-7.79
(m, 2H), 7.60 (d, 2H, J = 8.7 Hz), 4.14 (d, 2H, J = 6.0 Hz).
Example 5
[0152] Synthesis of N-[(4-hydroxy-2-oxo-7-(3-trifluoromethyl-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0153] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 406, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.58 (br s, 1H), 8.18 (s, 1H), 8.16 (s, 1H), 8.09 (d, 1H, J = 8.4 Hz), 7.97-7.76
(m, 4H), 4.15 (d, 2H, J = 6.0 Hz).
Example 6
Synthesis of N-[(4-hydroxy-2-oxo-7-(4-trifluoromethyl-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0154]
[0155] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 406, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.56 (br s, 1H), 8.11-8.05 (m, 3H), 7.91-7.84 (m, 4H), 4.15 (d, 2H, J = 6.0
Hz).
Example 7
Synthesis of N-[(4-hydroxy-2-oxo-7-(3-trifluoromethoxy-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0156]
[0157] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 422, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.57 (br s, 1H), 8.08 (d, 1H, J = 8.1 Hz), 7.92-7.85 (m, 4H), 7.69 (t, 1H),
7.50 (d, 1H, J = 8.4 Hz), 4.15 (d, 2H, J = 6.0 Hz).
Example 8
Synthesis of N-[(4-hydroxy-2-oxo-7-(4-trifluoromethoxy-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0158]
[0159] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 422, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.56 (br s, 1H), 8.09-7.81 (m, 5H), 7.54 (d, 2H, J = 8.4 Hz), 4.15 (d, 2H, J
= 6.0 Hz).
Example 9
Synthesis of N-[(4-hydroxy-2-oxo-7-(3,4-dichloro-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0160]
[0161] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 407, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.57 (br s, 1H), 8.15 (s, 1H), 8.05 (d, 1H, J = 8.1 Hz), 7.92-7.78 (m, 4H),
4.15 (d, 2H, J = 6.0 Hz).
Example 10
Synthesis of N-[(4-hydroxy-2-oxo-7-(3,4-difluoro-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0162]
[0163] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 374, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.55 (br s, 1H), 8.07-7.98 (m, 2H), 7.88-7.82 (m, 2H), 7.66-7.59 (m, 2H), 4.14
(d, 2H, J = 6.0 Hz).
Example 11
Synthesis of N-[(4-hydroxy-2-oxo-7-(3,4,5-trifluoro-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0164]
[0165] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 392, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.55 (br s, 1H), 8.05 (d, 1H, J = 8.4 Hz), 7.97-7.85 (m, 4H), 4.14 (d, 2H, J
= 6.0 Hz).
Example 12
Synthesis of N-[(4-hydroxy-2-oxo-7-(3-methoxy-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0166]
[0167] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 368, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.55 (br s, 1H), 8.05 (d, 1H, J = 8.1 Hz), 7.86 (s, 1H), 7.83 (d, 1H, J = 8.1
Hz), 7.49-7.38 (m, 3H), 7.06 (d, 1H, J = 8.4 Hz), 4.15 (d, 2H, J = 6.0 Hz).
Example 13
Synthesis of N-[(4-hydroxy-2-oxo-7-(4-methoxy-phenyl)-2H-3-chromenyl)carbonyl]glycine
[0168]
[0169] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 368, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.56 (br s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.85-7.78 (m, 4H), 7.09 (d, 2H, J
= 9.0 Hz), 4.14 (d, 2H, J = 6.0 Hz).
Example 14
Synthesis of N-[(4-hydroxy-2-oxo-7-(3-methylphenyl)-2H-3-chromenyl)carbonyl]glycine
[0170]
[0171] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 352, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.55 (br s, 1H), 8.04 (d, 1H, J = 8.7 Hz), 7.80-7.78 (m, 2H), 7.67-7.61 (m,
2H), 7.42 (t, 1H, 7.8 Hz), 7.30 (d, 1H, J = 7.5 Hz), 4.14 (d, 2H, J = 6.0 Hz), 2.50
(t, 3H, 1.8 Hz).
Example 15
Synthesis of N-[(4-hydroxy-2-oxo-7-(4-methylphenyl)-2H-3-chromenyl)carbonyl]glycine
[0172]
[0173] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 352, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.56 (br s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.79-7.73 (m, 4H), 7.34 (d, 2H, J
= 8.4 Hz), 4.13 (d, 2H, J = 6.0 Hz), 2.50 (t, 3H, 1.8 Hz).
Example 16
Synthesis of N-[(4-hydroxy-2-oxo-8-phenyl-2H-3-chromenyl)carbonyl]glycine
[0174]
[0175] Similar to the synthetic procedure of Example 1, Reagent
7 (27 g) was dissolved in 130 mL of AC
2O with addition of 1mL of H
3PO
4, and was heated at 50°C. After its completion, the reaction mixture was cooled to
room temperature, and 500 mL of water was then added in and stirred at 50°C until
hydrolyzation is complete. The reaction mixture was then cooled to 0°C and filtered.
The resulting solid, Compound
8, was further dried (24.4 g).
[0176] Compound
8 (13 g) and 1-Hydroxybenzotriazole anhydrous (HOBt, 6.8 g) was dissolved in 200 mL
of THF. Dicyclohexylcarbodiimide (DCC, 10.4 g) was gradually added in at 0°C and stirred
over night at a temperature below 10°C. The reaction mixture was filtered and the
Filtrate B was collected. 6.6 g (50 mmol)of dimethyl malonate was dissolved in 400
mL of THF first, then 3.8 g sodium hydride (70% dispersion) was added in. Filtrate
B was added while stirred and left to react for 2 hours at room temperature. After
THF removed by vacuum distillation, 200 mL of methanol and 200 mL of 10% HCl were
added and stirred over night. After filtration, the resulting solid was washed with
200 mL of methanol and dried, yielding 6 g of Compound
9.
[0177] Glycine t-butyl ester HCl salt (13.5 g) and sodium methoxide (4.4 g) were suspended
in 200 mL of methanol. After stirred to a homogeneous suspension, it was distilled
to remove all methanol. 200 mL of THF and Compound
9 (6.0 g) were added in and the reaction was run at 60°C over night. THF was then removed
by vacuum distillation and 400 mL of methanol was added and stirred for 2 hours. After
filtration and drying, it gave 3.5 g of Compound
10.
[0178] Compound
10 (240 mg, 0.6 mmol), Pd(PPh
3)
4 (140 mg, 0.12 mmol) and phenyl boronic acid (85.4 mg, 0.7 mmol) were dissolved in
1 mL of 2M Na
2CO
3 aqueous solution and 4 mL of DMF. The resulting solution was heated to 80°C under
nitrogen gas overnight. After its completion, the reaction mixture was cooled to room
temperature. 100mL of water and 100 mL of ethyl acetate were added and stirred. The
organic layer was retained and washed twice more by water, followed by quickly passing
through a silicon gel column to remove solvent. 5 mL of dichloromethane and 5 mL of
trifluoroacetic acid were then added and stirred at room temperature for 4 hrs. After
its completion, the reaction mixture was evaporated
in vacuo. The resulting product was further purified by recrystallization using CH
3OH-THF to arrive at the title compound
12, with the LC-MS [M-H]
- m/z 338, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.51 (br s, 1H), 8.03 (dd, 1H, J = 8.1, 1.5 Hz), 7.86 (dd, 2H, J = 7.5, 1.5
Hz), 7.65-7.45 (m, 6H), 4.15 (d, 2H, J = 6.0 Hz).
Example 17
Synthesis of N-[(4-hydroxy-2-oxo-8-(2-chlorophenyl)-2H-3-chromenyl)carbonyl]glycine
[0179]
[0180] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 373, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.47 (br s, 1H), 8.10 (m, 1H), 7.77 (m, 1H), 7.67-7.50 (m, 5H), 4.14 (d, 2H,
J = 6.0 Hz).
Example 18
Synthesis of N-[(4-hydroxy-2-oxo-8-(3-chlorophenyl)-2H-3-chromenyl)carbonyl]glycine
[0181]
[0182] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 373, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.51 (br s, 1H), 8.06 (dd, 1H, J = 8.1, 1.5 Hz), 7.89 (m, 1H), 7.73 (s, 1H),
7.61-7.54 (m, 4H), 4.15 (d, 2H, J = 6.0 Hz).
Example 19
Synthesis of N-[(4-hydroxy-2-oxo-8-(4-chlorophenyl)-2H-3-chromenyl)carbonyl]glycine
[0183]
[0184] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 373, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.49 (br s, 1H), 8.04 (dd, 1H, J = 8.1, 1.5 Hz), 7.86 (m, 1H), 7.69-7.53 (m,
5H), 4.15 (d, 2H, J = 6.0 Hz).
Example 20
Synthesis of N-[(4-hydroxy-2-oxo-8-(3-trifluoromethylphenyl)-2H-3-chromenyl)carbonyl]glycine
[0185]
[0186] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 406, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.52 (br s, 1H), 8.09-7.76 (m, 6H), 7.58 (t, 1H, 7.8 Hz), 4.15 (d, 2H, J = 6.0
Hz).
Example 21
Synthesis of N-[(4-hydroxy-2-oxo-8-(4-trifluoromethylphenyl)-2H-3-chromenyl)carbonyl]glycine
[0187]
[0188] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 406, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.50 (br s, 1H), 8.09 (dd, 1H, 7.8, 1.5 Hz), 7.93-7.86 (m, 5H), 7.59 (t, 1H,
7.8 Hz), 4.15 (d, 2H, J = 6.0 Hz).
Example 22
Synthesis of N-[(4-hydroxy-2-oxo-8-(3-trifluoromethoxyphenyl)-2H-3-chromenyl)carbonyl]glycine
[0189]
[0190] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 422, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.52 (br s, 1H), 8.07 (dd, 1H, 7.8, 1.5 Hz), 7.91 (dd, 1H, 7.5, 1.5 Hz), 7.70-7.68
(m, 3H), 7.57 (t, 1H, 7.8 Hz), 7.49 (br s, 1H), 4.15 (d, 2H, J = 6.0 Hz).
Example 23
Synthesis of N-[(4-hydroxy-2-oxo-8-(4-trifluoromethoxyphenyl)-2H-3-chromenyl)carbonyl]glycine
[0191]
[0192] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 422, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.50 (br s, 1H), 8.06 (dd, 1H, 8.1, 1.5 Hz), 7.89 (m, 1H), 7.78 (d, 2H, J =
8.7 Hz), 7.60-7.54 (m, 3H), 4.15 (d, 2H, J = 6.0 Hz).
Example 24
Synthesis of N-[(4-hydroxy-2-oxo-8-(3 ,4-dichlorophenyl)-2H-3-chromenyl)carbonyl]glycine
[0193]
[0194] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 407, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.51 (br s, 1H), 8.06 (dd, 1H, 8.1, 1.5 Hz), 7.95-7.89 (m, 2H), 7.82 (d, 1H,
J = 8.4 Hz), 7.65 (dd, 1H, J = 8.4, 1.5 Hz), 7.56 (t, 1H, J = 7.5 Hz), 4.15 (d, 2H,
J = 6.0 Hz).
Example 25
Synthesis of N-[(4-hydroxy-2-oxo-8-(3,4-difluorophenyl)-2H-3-chromenyl)carbonyl]glycine
[0195]
[0196] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 374, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.51 (br s, 1H), 7.88 (dd, 1H, J = 7.5, 1.2 Hz), 7.82-7.75 (m, 2H), 7.68 -7.53
(m, 3H), 4.15 (d, 2H, J = 6.0 Hz).
Example 26
Synthesis of N-[(4-hydroxy-2-oxo-8-(3,4,5-trifluorophenyl)-2H-3-chromenyl)carbonyl]glycine
[0197]
[0198] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 392, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.51 (br s, 1H), 8.07 (dd, 1H, J = 7.8, 1.5 Hz), 8.01-7.97 (m, 1H), 7.92 -7.89
(m, 1H), 7.71-7.66 (m, 1H), 7.63 (t, 1H, J = 7.8 Hz), 4.15 (d, 2H, J = 6.0 Hz).
Example 27
Synthesis of N-[(4-hydroxy-2-oxo-8-(3-methoxyphenyl)-2H-3-chromenyl)carbonyl]glycine
[0199]
[0200] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 368, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.52 (br s, 1H), 8.07 (dd, 1H, J = 7.8, 1.5 Hz), 7.87 (dd, 1H, J = 7.8, 1.5
Hz), 7.55 (t, 1H, J = 7.8 Hz), 7.45 (t, 1H, J = 7.8 Hz), 7.20-7.18 (m, 2H), 7.06-7.03
(m, 1H), 4.15 (d, 2H, J = 6.0 Hz).
Example 28
Synthesis of N-[(4-hydroxy-2-oxo-8-(4-methoxyphenyl)-2H-3-chromenyl)carbonyl]glycine
[0201]
[0202] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 368, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.51 (br s, 1H), 7.98 (d, 1H, J = 7.8 Hz), 7.83-7.80 (m, 1H), 7.59-7.50 (m,
3H), 7.09 (d, 2H, J = 8.7 Hz), 4.15 (d, 2H, J = 6.0 Hz).
Example 29
Synthesis of N-[(4-hydroxy-2-oxo-8-(3-methylphenyl)-2H-3-chromenyl)carbonyl]glycine
[0203]
[0204] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 352, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.52 (br s, 1H), 8.03 (dd, 1H, J = 7.8, 1.5 Hz), 7.84-7.82 (m, 1H), 7.57-7.52
(m, 1H), 7.43-7.42 (m, 3H), 7.29 (br s, 1H), 4.14 (d, 2H, J = 6.0 Hz), 2.51 (t, 3H,
J = 1.8 Hz).
Example 30
Synthesis of N-[(4-hydroxy-2-oxo-8-(4-methylphenyl)-2H-3-chromenyl)carbonyl]glycine
[0205]
[0206] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 352, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.53 (br s, 1H), 8.02-7.99 (m, 1H), 7.84-7.82 (m, 1H), 7.57-7.51 (m, 3H), 7.36-7.33
(m, 2H), 4.14 (d, 2H, J = 6.0 Hz), 2.51 (t, 3H, J = 1.8 Hz).
Example 31
Synthesis of N-[(4-hydroxy-2-oxo-7-(6-methoxypyridin-3-yl)-2H-3-chromenyl)carbonyl]glycine
[0207]
[0208] Similar procedure to Example 1 was followed to arrive at the title compound, with
the LC-MS [M-H]
- m/z 369, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.54 (br s, 1H), 8.69 (d, 1H, J = 1.8 Hz), 8.21 (dd, 1H, J = 8.7, 1.8 Hz), 8.023
(d, 1H, 8.1 Hz), 7.85-7.80 (m, 2H), 6.98 (d, 1H, 8.7 Hz), 4.14 (d, 2H, J = 6.0 Hz),
2.51 (m, 3H).
Example 32
Synthesis of N-[(4-hydroxy-2-oxo-7-(pyridin-4-yl)-2H-3-chromenyl)carbonyl]glycine
[0209]
[0210] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 339.
Example 33
Synthesis of N-[(4-hydroxy-2-oxo-7-(pyridin-3-yl)-2H-3 -chromenyl)carbonyl] glycine
[0211]
[0212] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 339, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.55 (br s, 1H), 9.12 (s, 1H), 8.73 (s, 1H), 8.38 (d, 1H, J = 8.1 Hz), 8.11
(d, 1H, J = 8.4 Hz), 7.97 (s, 1H), 7.90 (d, 1H, J = 8.4 Hz), 7.69-7.65 (m, 1H), 4.16
(d, 2H, J = 6.0 Hz).
Example 34
Synthesis of N-[(4-hydroxy-2-oxo-7-phenoxy-2H-3-chromenyl)carbonyl]glycine
[0213]
[0214] Similar procedure to the previous example was followed to arrive at the title compound,
with the LC-MS [M-H]
- m/z 354, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.47 (br s, 1H), 8.99 (d, 1H, 8.7 Hz), 7.55-7.49 (m, 2H), 7.33 (t, 1H, J = 7.5
Hz),7.24-7.21 (m, 2H), 7.05-7.01 (m, 1H), 6.96 (d, 1H, J = 2.4 Hz), 4.12 (d, 2H, J
= 6.0 Hz).
Example 35
Synthesis of N-[(4-hydroxy-2-oxo-7-bromo-3-chromenyl)carbonyl]glycine
[0215]
[0216] Synthesis was shown as of Compound
4 in Example 1, followed by similar procedure to de-protect the t-butyl group on the
carboxylate group to arrive at the title compound with the LC-MS [M-H]
- m/z 341, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.53 (br s, 1H), 7.93-7.86 (m, 2H), 7.68-7.65 (m, 1H), 4.14 (m, 2H).
Example 36
Synthesis of N-[(4-hydroxy-2-oxo-8-bromo-3 -chromenyl)carbonyl]glycine
[0217]
[0218] Synthesis was shown as of Compound
10 in Example 16, followed by similar procedure to de-protect the t-butyl group on the
carboxylate group to arrive at the title compound with the LC-MS [M-H]
- m/z 341, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.51 (br s, 1H), 8.12 (d, 1H, J = 7.8 Hz), 8.00 (d, 1H, J = 7.8 Hz), 7.40 (t,
1H, J = 7.8 Hz), 4.15 (d, 2H, J = 6.0 Hz).
Example 37
Synthesis of N-[(4-hydroxy-2-oxo-6-bromo-3-chromenyl)carbonyl]glycine
[0219]
[0220] Similar procedure to the previous example was followed to arrive at the title compound
with the LC-MS [M-H]
- m/z 341, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.56 (br s, 1H), 8.07 (d, 1H, J = 2.4 Hz), 7.99 (dd, 1H, J = 9.0, 2.4 Hz), 7.49
(d, 1H, J = 9.0 Hz), 4.14 (d, 2H, J = 6.0 Hz).
Example 38
Synthesis of N-[(4-hydroxy-2-oxo-8-(3-trifluoromethylphenyl)-2H-3-chromenyl)carbonyl]alanine
[0221]
[0222] Similar procedure to Example 20 was followed, except that an alanine t-butyl ester
was used instead of a glycine t-butyl ester, to arrive at the title compound, with
the LC-MS [M-H]
- m/z 420, and
1H-NMR (300 MHz, (CD
3)
2SO) δ 9.59 (br s, 1H), 8.09-8.03 (m, 2H), 7.95 (dd, 2H, J = 7.5, 1.5 Hz), 7.86-7.76
(m, 2H), 7.59 (t, 1H, 7.5 Hz), 4.57 (m, 1H), 1.48 (d, 1H, J = 7.2 Hz).
Example A. Assay of HIF-PHD2 Enzyme Activity
[0223] HIF-PHD2 activity was measured using homogeneous TR-FRET technology (see also,
US2008/004817;
Dao JH et al., Anal Biochem. 2009, 384:213-23). To each well of a 1/2Area 96-well plate was added 2 µL of test compound in DMSO
and 40 µL of assay buffer (50 mM Tris PH7.4/0.01% Tween-20/0.1 mg/ml BSA/1 mM Sodium
ascorbate/20 µg/ml Catalase/10 µM FeSO4) containing 600 nM full length PHD2. After
a 30 min preincubation at room temperature, the enzymatic reactions were initiated
by the addition of 8 µL of substrates(final concentrations of 0.2 µM 2-oxoglutarate
and 0.5 µM HIF-1α peptide biotinyl-DLDLEMLAPYIPMDDDFQL). After 2 hr at room temperature,
the reactions were terminated and signals were developed by the addition of a 50 µL
quench/detection mix to a final concentration of 1 mM ortho-phenanthroline, 0.1 mM
EDTA, 0.5 nM anti-(His)
6LANCE reagent, 100 nM AF647-labeled Streptavidin, and 30 nM (His)
6- VHL-elonginB-elonginC complex. The ratio of time resolved fluorescence signals at
665 and 620 nm was determined, and percent inhibition was calculated relative to an
uninhibited control sample run in parallel.
Example B. Determination of Erythropoietin (EPO) Induction in Normal Mice
Example C. Determination of Hematology in Normal Mice
[0225] Eight-week-old male C57BL/6 mice were dosed orally with test compound at 60 mg/kg
once a day for a week. Blood samples were obtained from the orbital venous plexus
with time points including 1, 3 and 5 days after dosing. An Automated Hematology Analyzer
MEK-6318K was used to determine hematological parameters such as erythrocyte counts
(RBC), hemoglobin concentration (HGB), hematocrit value (HCT).
Example D. Pharmacokenetics Studies
[0226] Test compounds were administered in solution as a single oral dose to fasted male
CD (SD) IGS rats (n=6/group) at 50 mg/kg. Plasma samples were obtained from the orbital
venous plexus of each individual animal at 15', 30', 1h, 2h, 4h, 6h, 12h and 24h post-administration.
Compound blood concentrations in the plasma samples were measured by HPLC.
[0227] The IC
50 values for certain example compounds of invention in the Enzyme Assay of Example
A are provided in Table 1 as follows.
Table 1
COMPOUND |
Enzyme Assay IC50 (nM) |
Example 1 |
250 |
Example 2 |
150 |
Example 3 |
150 |
Example 4 |
150 |
Example 5 |
150 |
Example 6 |
150 |
Example 7 |
150 |
Example 8 |
150 |
Example 9 |
150 |
Example 10 |
150 |
Example 11 |
150 |
Example 12 |
150 |
Example 13 |
150 |
Example 14 |
300 |
Example 15 |
150 |
Example 16 |
350 |
Example 17 |
200 |
Example 18 |
90 |
Example 19 |
150 |
Example 20 |
100 |
Example 21 |
90 |
Example 22 |
100 |
Example 23 |
150 |
Example 24 |
30 |
Example 25 |
150 |
Example 26 |
150 |
Example 27 |
150 |
STRUCTURE |
Enzyme Assay IC50 (nM) |
[0228] All features disclosed in the specification, including the abstract and drawings,
and all the steps in any method or process disclosed, may be combined in any combination,
except combinations where at least some of such features and/or steps are mutually
exclusive.
1. A compound of Formula I:
or a pharmaceutically acceptable salt, solvate, or chelate thereof, wherein:
n is 1 to 6;
R1 is OH, SH, NR3R4, NHC(O)R2, NHSO2R2 or sulfonyl;
R2 is H, C1-6 alkyl or substituted C1-6 alkyl;
R3 and R4 are each independently H, C1-6 alkyl, substituted C1-6 alkyl, C1-6 haloalkyl, substituted C1-6 haloalkyl; or at least one pair of R3 and R4, together with the same carbon atom to which they are attached, may join to form
a 3 to 6 membered ring or a substituted 3 to 6 membered ring;
R5 is OH, SH, NH2, C1-6 alkyl, substituted C1-6 alkyl, C1-6 alkoxy, substituted C1-6 alkoxy, or sulfanyl;
each of R6 and R7 is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, NR3R4, C(O)OH, OR12, SR12, SO2R12, CN, NO2, halo, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted heteroarylalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylsilyl,
substituted alkylsilyl, alkynylsilyl, substituted alkynylsilyl, alkoxy, substituted
alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, or -X-R11; or R6 and R7, together with the carbon atoms to which they are attached, join to form a 4 to 7
membered ring or a substituted 4 to 7 membered ring;
X is -N(R10)-Y- or -Y-N(R10)-;
Y is C(O), SO2, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene,
or substituted alkynylene;
R8 is H, heteroaryl, substituted heteroaryl, phenyl, or phenyl substituted by halogen,
alkyl, alkoxy, haloalkyl, or haloalkoxy wherein at least one of R8 and R9 is phenyl substituted with halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy at the
para- or meta- position; or wherein one of R8 and R9 is phenyl substituted with halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy at the
para- or meta- position; and the other of R8 and R9 is H, halogen, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy; or wherein one of R8 and R9 is phenyl substituted with halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy at the
para- or meta- position; and the other of R8 and R9 is H;
R10 is H, C1-6 alkyl, or substituted C1-6 alkyl;
R11 is H, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl,
or substituted heteroaryl; and
R12 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl or NR3R4; wherein substituted refers to a group in which one or more hydrogen atoms are each
independently replaced with the same or different substituent(s) wherein substituents
include -X, -R33, -OH, =O, -OR33, SR33, -SH, =S, -NR33R34, =NR33, -CX3, -CF3, -CN, -NO2, -S(O)2R33,-OS(O2)OH, -OS(O)2R33, -OP(O)(OR33)(OR34), -C(O)R33, -C(S)R33, -C(O)OR33, -C(O)NR33R34, -C(O)OH, -C(S)OR33, -NR35C(O)NR33R34, -NR35C(S)NR33R34, -NR35C(NR33)NR33R34,-C(NR33)NR33R34, -S(O)2NR33R34, -NR35S(O)2R33, -NR35C(O)R33, and S(O)R33 where each X is independently a halo; each R33 and R34 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted
heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted
heteroarylalkyl, -NR35R36, -C(O)R35 or -S(O)2R35 or optionally R33 and R34 together with the atom to which R33 and R34 are attached form one or more heterocycloalkyl, substituted heterocycloalkyl, heteroaryl,
or substituted heteroaryl rings; and R35 and R36 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted
heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl, or optionally R35 and R36 together with the nitrogen atom to which R35 and R36 are attached form one or more heterocycloalkyl, substituted heterocycloalkyl, heteroaryl,
or substituted heteroaryl rings.
2. The compound of claim 1, wherein R1 is OH or SH.
3. The compound of claim 1, wherein R1 is OH.
4. The compound of any one of claims 1-3, wherein R2 is H or C1-6 alkyl,
5. The compound of any one of claims 1-3, wherein R2 is H.
6. The compound of any one of claims 1-5, wherein R3 and R4 are each independently H, C1-6 alkyl, or C1-6 haloalkyl.
7. The compound of any one of claims 1-5, wherein R3 and R4 are each independently H or C1-6 alkyl.
8. The compound of any one of claims 1-5, wherein R3 and R4 are each H.
9. The compound of any one of claims 1-8, wherein R5 is OH, SH, NH2, or C1-6 alkoxy.
10. The compound of any one of claims 1-8, wherein R5 is OH.
11. The compound of any one of claims 1-10, wherein at least one of R6 and R7 is halo or a moiety substituted with at least one halo.
12. The compound of any one of claims 1-10, wherein at least one of R6 and R7 is independently alkoxy or substituted alkoxy.
13. The compound of any one of claims 1-10, wherein at least one of R6 and R7 is independently aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl,
or substituted heterocycloalkyl.
14. The compound of any one of claims 1-13, wherein R8 is substituted phenyl or substituted heteroaryl.
15. The compound of any one of claims 1-13, wherein one of R8 and R9 is substituted phenyl, or R8 is substituted pyridyl.
16. The compound of any one of claims 1-13, wherein one of R8 and R9 is phenyl or phenyl substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy
at the para- and/or meta-position.
17. The compound of any one of claims 1-13, wherein R8 is pyridyl or pyridyl substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy
at the para- and/or meta- position.
18. The compound of claim 1, wherein the compound is a compound of Formula II:
wherein:
R21 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;
R22 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;
Z1 is CR23; and R23 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;
provided that at least one of R21 and R22 and R23, if present, is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.
19. The compound of claim 18, wherein R21 is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
20. The compound of claim 18, wherein R22 is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
21. The compound of claim 18, wherein R23 is H, CI, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
22. The compound of claim 18, wherein one of R21, R22, and R23 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and the other two of R21, R22, and R23 are each H.
23. The compound of claim 18, wherein one of R21 and R23 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and the other one of R21 and R23 is H.
24. The compound of claim 23, wherein R22 is H.
25. The compound of claim 18, wherein two of R21, R22, and R23 are each independently halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and the other one of R21, R22, and R23 is H.
26. The compound of claim 25, wherein R22 is H.
27. The compound of claim 18, wherein R21, R22, and R23 are each independently halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.
28. The compound of claim 18, wherein one of R21 and R22 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and the other of R21 and R22 is H.
29. The compound of claim 18, wherein the compound is of Formula IIa:
wherein:
R21 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and
R22 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;
provided that at least one of R21 and R22 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.
30. The compound of claim 29, wherein R21 is H; and R22 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.
31. The compound of claim 29, wherein R21 is H; and R22 is C1-6 alkyl or C1-6 haloalkyl.
32. The compound of claim 31, wherein R22 is methyl or C1-2 haloalkyl.
33. The compound of claim 31, wherein R22 is methyl or ethyl.
34. The compound of claim 29, wherein R22 is H; and R21 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.
35. The compound of claim 29, wherein R22 is H; and R21 is C1-6 alkyl or C1-6 haloalkyl.
36. The compound of claim 35, wherein R21 is methyl or C1-2 haloalkyl.
37. The compound of claim 35, wherein R21 is methyl or ethyl,
38. The compound of claim 29, wherein R21 and R22 are each independently halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.
39. The compound of claim 29, wherein R21 and R22 are each independently C1-2 alkyl or C1-2 haloalkyl.
40. The compound of claim 1, wherein the compound is of Formula III:
wherein:
R24 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;
R25 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;
Z2 is N or CR26; and R26 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;
provided that at least one of R24 and R25 and R26, if present, is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.
41. The compound of claim 40, wherein Z2 is CR26.
42. The compound of claim 40 or 41, wherein R24 is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
43. The compound of any one of claims 40-42, wherein R25 is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
44. The compound of any one of claims 40-43, wherein Z2 is CR26; R26 is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
45. The compound of claim 40, wherein Z2 is CR26; one of R24, R25, and R26 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and the other two of R24, R25, and R26 are each H.
46. The compound of claim 40, wherein Z2 is CR26; one of R24 and R26 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and the other one of R24 and R26 is H.
47. The compound of claim 40, wherein Z2 is CR26; two of R24, R25, and R26 are each independently halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and the other one of R24, R25, and R26 is H.
48. The compound of claim 40, wherein Z2 is CR26; R24, R25, and R26 are each independently halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy,
49. The compound of claim 40, wherein Z2 is N.
50. The compound of claim 49, wherein one of R24 and R25 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and the other of R24 and R25 is H.
51. The compound of claim 40, wherein the compound is of Formula IIIa:
wherein:
R24 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; and
R25 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;
provided that at least one of R24 and R25 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.
52. The compound of claim 51, wherein R24 is H; and R25 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.
53. The compound of claim 52, wherein R25 is methyl or C1-2 haloalkyl.
54. The compound of claim 51, wherein R25 is H; and R24 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.
55. The compound of claim 54, wherein R24 is methyl or C1-2 haloalkyl.
56. The compound of claim 51, wherein R24 and R25 are each independently halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.
57. The compound of claim 1, wherein the compound is:
2-(4-hydroxy-2-oxo-7-phenyl-2H-chromene-3-carboxamido)acetic acid;
2-(7-(2-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(7-(3-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(7-(4-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-7-(4-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-7-(3-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-7-(4-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(7-(3,4-dichlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(7-(3,4-difluorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-(3,4,5-trifluorophenyl)-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-7-(3-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-7-(4-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-m-tolyl-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-p-tolyl-2H-chromene-3-carboxamido)acetic acid;
2-(8-(2-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(8-(3-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(8-(4-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-8-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-8-(4-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-8-(3-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(4-hydroxy-2-oxo-8-(4-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic
acid;
2-(8-(3,4-dichlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(8-(3,4-difluorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-8-(3,4,5-trifluorophenyl)-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-8-(3-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-8-(4-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-8-m-tolyl-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-8-p-tolyl-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-7-(6-methoxypyridin-3-yl)-2-oxo-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-(pyridin-4-yl)-2H-chromene-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-7-(pyridin-3-yl)-2H-chromene-3-carboxamido)acetic acid; or
2-(4-hydroxy-2-oxo-8-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic
58. A pharmaceutical composition comprising a pharmaceutically acceptable excipient, adjuvant
or carrier, and a therapeutically effective amount of a compound of any one of claims
1-57.
59. The pharmaceutical composition of claim 58, further comprising an erythropoiesis stimulating
agent or a chemotherapeutic agent.
60. The pharmaceutical composition of claim 58, wherein the compound of any one of claims
1-57 is present in an amount effective for the treatment of ischemia, anemia, wound
healing, auto-transplantation, allo-transplantation, xeno-transplantation, systemic
high blood pressure, thalassemia, diabetes, cancer, an inflammatory disorder, or a
combination thereof.
61. The pharmaceutical composition of claim 58, wherein the compound of any one of claims
1-57 is present in an amount effective for the treatment of a disease, disorder or
condition associated with the HIF level or HIF activity which is ischemia, anemia,
wound healing, auto-transplantation, allo-transplantation, xeno-transplantation, systemic
high blood pressure, thalassemia, diabetes, cancer, an inflammatory disorder, or a
combination thereof.
62. Use of a compound of any one of claims 1-57 in the manufacture of a medicament for
the treatment of a disease, disorder, or condition which is ischemia, anemia, wound
healing, auto-transplantation, allo-transplantation, xeno-transplantation, systemic
high blood pressure, thalassemia, diabetes, cancer, an inflammatory disorder, or a
combination thereof.
1. Verbindung der Formel I:
oder ein pharmazeutisch annehmbares Salz, Solvat oder Chelat davon, worin:
n 1 bis 6 ist;
R1 OH, SH, NR3R4, NHC(O)R2, NHSO2R2 oder Sulfonyl ist;
R2 H, C1-6-Alkyl oder substituiertes C1-6-Alkyl is;
R3 und R4 jeweils unabhängig H, C1-6-Alkyl, substituiertes C1-6-Alkyl, C1-6-Haloalkyl, substituiertes C1-6-Haloalkyl sind, oder mindestens ein Paar von R3 und R4 kann zusammen mit dem selben Kohlenstoffatom, an das sie gebunden sind, einen 3-
bis 6-gliedrigen Ring oder einen substituierten 3- bis 6-gliedrigen Ring bilden;
R5 OH, SH, NH2, C1-6-Alkyl, substituiertes C1-6-Alkyl, C1-6-Alkoxy, substituiertes C1-6-Alkoxy oder Sulfanyl ist;
jedes von R6 und R7 unabhängig H, Alkyl, substituiertes Alkyl, Alkenyl, substituiertes Alkenyl, Alkinyl,
substituiertes Alkinyl, NR3R4, C(O)OH, OR12, SR12, SO2R12, CN, NO2, Halogen, Aryl, substituiertes Aryl, Heteroaryl, substituiertes Heteroaryl, Heteroarylalkyl,
substituiertes Heteroarylalkyl, Heterocycloalkyl, substituiertes Heterocycloalkyl,
Alkylsilyl, substituiertes Alkylsilyl, Alkinylsilyl, substituiertes Alkinylsilyl,
Alkoxy, substituiertes Alkoxy, Alkoxycarbonyl, substituiertes Alkoxycarbonyl oder
-X-R11 ist, oder R6 und R7 bilden zusammen mit den Kohlenstoffatomen, an die sie gebunden sind, einen 4- bis
7-gliedrigen Ring oder einen substituierten 4- bis 7-gliedrigen Ring;
X-N(R10)-Y- oder -Y-N(R10)- ist;
Y C(O), SO2, Alkylen, substituiertes Alkylen, Alkenylen, substituiertes Alkenylen, Alkinylen
oder substituiertes Alkinylen ist;
R8 H, Heteroaryl, substituiertes Heteroaryl, Phenyl oder Phenyl, das mit Halogen, Alkyl,
Alkoxy, Haloalkyl oder Haloalkoxy substituiert ist, ist, wobei mindestens eines von
R8 und R9 Phenyl ist, das an para- oder meta-Position mit Halogen, Alkyl, Haloalkyl, Alkoxy
oder Haloalkoxy substituiert ist, oder
wobei eines von R8 und R9 Phenyl ist, das an para- oder meta-Position mit Halogen, Alkyl, Haloalkyl, Alkoxy
oder Haloalkoxy substituiert ist, und das andere von R8 und R9 H, Halogen, OH, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist, oder wobei eines von R8 und R9 Phenyl ist, das an para- oder meta-Position mit Halogen, Alkyl, Haloalkyl, Alkoxy
oder Haloalkoxy substituiert ist, und das andere von R8 und R9 H ist;
R10 H, C1-6-Alkyl oder substituiertes C1-6-Alkyl ist;
R11 H, Heterocycloalkyl, substituiertes Heterocycloalkyl, Aryl, substituiertes Aryl,
Heteroaryl oder substituiertes Heteroaryl ist; und
R12 H, Alkyl, substituiertes Alkyl, Alkenyl, substituiertes Alkenyl, Alkinyl, substituiertes
Alkinyl oder NR3R4 ist, wobei substitutiert sich auf eine Gruppe bezieht, in der ein oder mehrere Wasserstoffatome
jeweils unabhängig durch den gleichen oder durch unterschiedliche Substituenten ersetzt
ist/sind, wobei Substituenten -X, -R33, -OH, =O, -OR33, SR33, -SH, =S, -NR33R34, =NR33, -CX3, -CF3, -CN, -NO2, -S(O)2R33, -OS(O2)OH, -OS(O)2R33, -OP(O)(OR33)(OR34),-C(O)R33, -C(S)R33, -C(O)OR33, -C(O)NR33R34, -C(O)OH, -C(S)OR33,-NR35C(O)NR33R34, -NR35C(S)NR33R34, -NR35C(NR33)NR33R34,-C(NR33)NR33R34, -S(O)2NR33R34, -NR35S(O)2R33, -NR35C(O)R33 und S(O)R33 beinhalten, wobei jedes X unabhängig Halogen ist, jedes R33 und R34 unabhängig Wasserstoff, Alkyl, substituiertes Alkyl, Aryl, substituiertes Aryl, Arylalkyl,
substituiertes Arylalkyl, Cycloalkyl, substituiertes Cycloalkyl, Heterocycloalkyl,
substituiertes Heterocycloalkyl, Heteroaryl, substituiertes Heteroaryl, Heteroarylalkyl,
substituiertes Heteroarylalkyl, -NR35R36, -C(O)R35 oder -S(O)R35 ist oder R33 und R34 gegebenenfalls mit dem Atom, an das R33 und R34 gebunden sind, einen oder mehrere Heterocycloalkyl-, substituierte Heterocycloalkyl-,
Heteroaryl- oder substituierte Heteroarylringe bilden; und
R35 und R36 unabhängig Wasserstoff, Alkyl, substituiertes Alkyl, Aryl, substituiertes Aryl, Arylalkyl,
substituiertes Arylalkyl, Cycloalkyl, substituiertes Cycloalkyl, Heterocycloalkyl,
substituiertes Heterocycloalkyl, Heteroaryl, substituiertes Heteroaryl, Heteroarylalkyl
oder substituiertes Heteroarylalkyl sind, oder gegebenenfalls R35 und R36 zusammen mit dem Stickstoffatom, an das R35 und R36 gebunden sind, einen oder mehrere Heterocycloalkyl-, substituierte Heterocycloalkyl-,
Heteroaryl- oder substituierte Heteroarylringe bilden.
2. Verbindung nach Anspruch 1, wobei R1 OH oder SH ist.
3. Verbindung nach Anspruch 1, wobei R1 OH ist.
4. Verbindung nach einem der Ansprüche 1-3, wobei R2 H oder C1-6-Alkyl ist.
5. Verbindung nach einem der Ansprüche 1-3, wobei R2 H ist.
6. Verbindung nach einem der Ansprüche 1-5, wobei R3 und R4 jeweils unabhängig H, C1-6-Alkyl oder C1-6-Haloalkyl sind.
7. Verbindung nach einem der Ansprüche 1-5, wobei R3 und R4 jeweils unabhängig H oder C1-6-Alkyl sind.
8. Verbindung nach einem der Ansprüche 1-5, wobei R3 und R4 jeweils H sind.
9. Verbindung nach einem der Ansprüche 1-8, wobei R5 OH, SH, NH2 oder C1-6-Alkoxy ist.
10. Verbindung nach einem der Ansprüche 1-8, wobei R5 OH ist.
11. Verbindung nach einem der Ansprüche 1-10, wobei mindestens eines von R6 und R7 Halogen oder eine Gruppe, die mit mindestens einem Halogen substituiert ist, ist.
12. Verbindung nach einem der Ansprüche 1-10, wobei mindestens eines von R6 und R7 unabhängig Alkoxy oder substituiertes Alkoxy ist.
13. Verbindung nach einem der Ansprüche 1-10, wobei mindestens eines von R6 und R7 unabhängig Aryl, substituiertes Aryl, Heteroaryl, substituiertes Heteroaryl, Heterocycloalkyl
oder substituiertes Heterocycloalkyl ist.
14. Verbindung nach einem der Ansprüche 1-13, wobei R8 substituiertes Phenyl oder substituiertes Heteroaryl ist.
15. Verbindung nach einem der Ansprüche 1-13, wobei eines von R8 und R9 substituiertes Phenyl ist oder R8 substituiertes Pyridyl ist.
16. Verbindung nach einem der Ansprüche 1-13, wobei eines von R8 und R9 Phenyl oder Phenyl, das an para- und/oder meta-Position mit Halogen, Alkyl, Haloalkyl,
Alkoxy oder Haloalkoxy substituiert ist, ist.
17. Verbindung nach einem der Ansprüche 1- 13, wobei R8 Pyridyl oder Pyridyl, das an para- und/oder meta-Position mit Halogen, Alkyl, Haloalkyl,
Alkoxy oder Haloalkoxy substituiert ist, ist.
18. Verbindung nach Anspruch 1, wobei die Verbindung eine Verbindung der Formel II ist:
worin
R21 H, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist;
R22 H, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist;
Z1 CR23 ist; und R23 H, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist;
unter der Voraussetzung, dass mindestens eines von R21 und R22 und R23, falls vorhanden, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist.
19. Verbindung nach Anspruch 18, wobei R21 H, Cl, F, Methyl, Ethyl, Trifluoromethyl, Methoxy, Ethoxy oder Trifluoromethoxy ist.
20. Verbindung nach Anspruch 18, wobei R22 H, Cl, F, Methyl, Ethyl, Trifluoromethyl, Methoxy, Ethoxy oder Trifluoromethoxy ist.
21. Verbindung nach Anspruch 18, wobei R23 H, Cl, F, Methyl, Ethyl, Trifluoromethyl, Methoxy, Ethoxy oder Trifluoromethoxy ist.
22. Verbindung nach Anspruch 18, wobei eines von R21, R22 und R23 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist und die anderen beiden von R21, R22 und R23 jeweils H sind.
23. Verbindung nach Anspruch 18, wobei eines von R21 und R23 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist und das andere von R21 und R23 H ist.
24. Verbindung nach Anspruch 23, wobei R22 H ist.
25. Verbindung nach Anspruch 18, wobei zwei von R21, R22 und R23 jeweils unabhängig Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy sind und das andere von R21, R22 und R23 H ist.
26. Verbindung nach Anspruch 25, wobei R22 H ist.
27. Verbindung nach Anspruch 18, wobei R21, R22 und R23 jeweils unabhängig Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy sind.
28. Verbindung nach Anspruch 18, wobei eines von R21 und R22 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist und das andere von R21 und R22 H ist.
29. Verbindung nach Anspruch 18, wobei die Verbindung die Formel IIa hat:
worin:
R21 H, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist;
R22 H, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist;
unter der Voraussetzung, dass mindestens eines von R21 und R22 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist.
30. Verbindung nach Anspruch 29, wobei R21 H ist und R22 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist.
31. Verbindung nach Anspruch 29, wobei R21 H ist und R22 C1-6-Alkyl oder C1-6-Haloalkyl ist.
32. Verbindung nach Anspruch 31, wobei R22 Methyl oder C1-2-Haloalkyl ist.
33. Verbindung nach Anspruch 31, wobei R22 Methyl oder Ethyl ist.
34. Verbindung nach Anspruch 29, wobei R22 H ist und R21 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist.
35. Verbindung nach Anspruch 29, wobei R22 H ist und R21 C1-6-Alkyl oder C1-6-Haloalkyl ist.
36. Verbindung nach Anspruch 35, wobei R21 Methyl oder C1-2-Haloalkyl ist.
37. Verbindung nach Anspruch 35, wobei R21 Methyl oder Ethyl ist.
38. Verbindung nach Anspruch 29, wobei R21 und R22 jeweils unabhängig Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy sind.
39. Verbindung nach Anspruch 29, wobei R21 und R22 jeweils unabhängig C1-2-Alkyl oder C1-2-Haloalkyl sind.
40. Verbindung nach Anspruch 1, wobei die Verbindung die Formel III hat:
worin:
R24 H, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist;
R25 H, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist;
Z2 N oder CR26 ist; und R26 H, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist;
unter der Voraussetzung, dass mindestens eines von R24 und R25 und R26, falls vorhanden, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist.
41. Verbindung nach Anspruch 40, wobei Z2 CR26 ist.
42. Verbindung nach Anspruch 40 oder 41, wobei R24 H, Cl, F, Methyl, Ethyl, Trifluoromethyl, Methoxy, Ethoxy oder Trifluoromethoxy ist.
43. Verbindung nach einem der Ansprüche 40-42, wobei R25 H, Cl, F, Methyl, Ethyl, Trifluoromethyl, Methoxy, Ethoxy oder Trifluoromethoxy ist.
44. Verbindung nach einem der Ansprüche 40-43, wobei Z2 CR26 ist und R26 H, Cl, F, Methyl, Ethyl, Trifluoromethyl, Methoxy, Ethoxy oder Trifluoromethoxy ist.
45. Verbindung nach Anspruch 40, wobei Z2 CR26 ist, eines von R24, R25 und R26 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist und die anderen beiden von R24, R25 und R26 jeweils H sind.
46. Verbindung nach Anspruch 40, wobei Z2 CR26 ist, eines von R24 und R26 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist und das andere von R24 und R26 H ist.
47. Verbindung nach Anspruch 40, wobei Z2 CR26 ist, zwei von R24, R25 und R26 jeweils unabhängig Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy sind und das andere von R24, R25 und R26 H ist.
48. Verbindung nach Anspruch 40, wobei Z2 CR26 ist und R24, R25 und R26 jeweils unabhängig Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy sind.
49. Verbindung nach Anspruch 40, wobei Z2 N ist.
50. Verbindung nach Anspruch 49, wobei eines von R24 und R25 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist und das andere von R24 und R25 H ist.
51. Verbindung nach Anspruch 40, wobei die Verbindung die Formel IIa hat:
worin:
R24 H, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist; und
R25 H, Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist;
unter der Voraussetzung, dass mindestens eines von R24 und R25 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist.
52. Verbindung nach Anspruch 51, wobei R24 H ist und R25 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist.
53. Verbindung nach Anspruch 52, wobei R25 Methyl oder C1-2-Haloalkyl ist.
54. Verbindung nach Anspruch 51, wobei R25 H ist und R24 Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy ist.
55. Verbindung nach Anspruch 54, wobei R24 Methyl oder C1-2-Haloalkyl ist.
56. Verbindung nach Anspruch 51, wobei R24 und R25 jeweils unabhängig Halogen, C1-6-Alkyl, C1-6-Haloalkyl, C1-6-Alkoxy oder C1-6-Haloalkoxy sind.
57. Verbindung nach Anspruch 1, wobei die Verbindung
2-(4-Hydroxy-2-oxo-7-phenyl-2H-chromen-3-carboxamido)essigsäure;
2-(7-(2-Chlorophenyl)-4-hydroxy-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(7-(3-Chlorophenyl)-4-hydroxy-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(7-(4-Chlorophenyl)-4-hydroxy-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-7-(3-(trifluoromethyl)phenyl)-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-7-(4-(trifluoromethyl)phenyl)-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-7-(3-(trifluoromethoxy)phenyl)-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-7-(4-(trifluoromethoxy)phenyl)-2H-chromen-3-carboxamido)essigsäure;
2-(7-(3,4-Dichlorophenyl)-4-hydroxy-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(7-(3,4-Difluorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-7-(3,4,5-trifluorophenyl)-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-7-(3-methoxyphenyl)-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-7-(4-methoxyphenyl)-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-7-m-tolyl-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-7-p-tolyl-2H-chromen-3-carboxamido)essigsäure;
2-(8-(2-Chlorophenyl)-4-hydroxy-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(8-(3-Chlorophenyl)-4-hydroxy-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(8-(4-Chlorophenyl)-4-hydroxy-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-8-(3-(trifluoromethyl)phenyl)-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-8-(4-(trifluoromethyl)phenyl)-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-8-(3-(trifluoromethoxy)phenyl)-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-8-(4-(trifluoromethoxy)phenyl)-2H-chromen-3-carboxamido)essigsäure;
2-(8-(3,4-Dichlorophenyl)-4-hydroxy-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(8-(3,4-Difluorophenyl)-4-hydroxy-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-8-(3,4,5-trifluorophenyl)-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-8-(3-methoxyphenyl)-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-8-(4-methoxyphenyl)-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-8-m-tolyl-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-8-p-tolyl-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-7-(6-methoxypyridin-3-yl)-2-oxo-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-7-(pyridin-4-yl)-2H-chromen-3-carboxamido)essigsäure;
2-(4-Hydroxy-2-oxo-7-(pyridin-3-yl)-2H-chromen-3-carboxamido)essigsäure; oder
2-(4-Hydroxy-2-oxo-8-(3-(trifluoromethyl)phenyl)-2H-chromen-3-carboxamido)essigsäure
ist.
58. Pharmazeutische Zusammensetzung umfassend ein/einen pharmazeutisch annehmbares/n Bindemittel
(excipient), Hilfsstoff oder Träger und eine therapeutisch wirksame Menge von einer
Verbindung nach einem der Ansprüche 1-57.
59. Pharmazeutische Zusammensetzung nach Anspruch 58, ferner umfassend ein Erythropoese-stimulierendes
Mittel oder ein Chemotherapeutikum.
60. Pharmazeutische Zusammensetzung nach Anspruch 58, wobei die Verbindung nach einem
der Ansprüche 1-57 in einer Menge vorhanden ist, die zur Behandlung von Ischämie,
Anämie, Wundheilung, Autotransplantation, Allotransplantation, Xenotransplantation,
systemischem Bluthochdruck, Thalassämie, Diabetes, Krebs, einer entzündlichen Erkrankung
oder einer Kombination davon wirksam ist.
61. Pharmazeutische Zusammensetzung nach Anspruch 58, wobei die Verbindung nach einem
der Ansprüche 1-57 in einer Menge vorhanden ist, die zur Behandlung einer Krankheit,
Störung oder eines Zustands, die/der mit dem HIF-Spiegel oder HIF-Aktivität im Zusammenhang
steht, und die/der Ischämie, Anämie, Wundheilung, Autotransplantation, Allotransplantation,
Xenotransplantation, systemischer Bluthochdruck, Thalassämie, Diabetes, Krebs, eine
entzündliche Erkrankung oder eine Kombination davon ist, wirksam ist.
62. Verwendung einer Verbindung nach einem der Ansprüche 1-57 in der Herstellung eines
Medikaments zur Behandlung einer Krankheit, Störung oder eines Zustands, die/der Ischämie,
Anämie, Wundheilung, Autotransplantation, Allotransplantation, Xenotransplantation,
systemischer Bluthochdruck, Thalassämie, Diabetes, Krebs, eine entzündliche Erkrankung
oder eine Kombination davon ist.
1. Composé de Formule I :
ou un sel, solvate, ou chélate pharmaceutiquement acceptable de celui-ci, dans lequel
:
n est 1 à 6 ;
R1 est OH, SH, NR3R4, NHC(O)R2, NHSO2R2 ou un sulfonyle ;
R2 est H, un C1-6 alkyle ou un C1-6 alkyle substitué ;
R3 et R4 sont chacun indépendamment H, un C1-6 alkyle, un C1-6 alkyle substitué, un C1-6 haloalkyle, un C1-6 haloalkyle substitué ; ou au moins une paire de R3 et R4, avec le même atome de carbone auquel ils sont attachés, peuvent se joindre pour
former un cycle de 3 à 6 chaînons ou un cycle de 3 à 6 chaînons substitué ;
R5 est OH, SH, NH2, un C1-6 alkyle, un C1-6 alkyle substitué, un C1-6 alcoxy, un C1-6 alcoxy substitué, ou un sulfanyle ;
chacun de R6 et R7 est indépendamment H, un alkyle, un alkyle substitué, un alcényle, un alcényle substitué,
un alcynyle, un alcynyle substitué, NR3R4, C(O)OH, OR12, SR12, SO2R12, CN, NO2, un halo, un aryle, un aryle substitué, un hétéroaryle, un hétéroaryle substitué,
un hétéroarylalkyle, un hétéroarylalkyle substitué, un hétérocycloalkyle, un hétérocycloalkyle
substitué, un alkylsilyle, un alkylsilyle substitué, un alcynylsilyle, un alcynylsilyle
substitué, un alcoxy, un alcoxy substitué, un alcoxycarbonyle, un alcoxycarbonyle
substitué, ou -X-R11 ; ou R6 et R7, avec les atomes de carbone auxquels ils sont attachés, se joignent pour former un
cycle de 4 à 7 chaînons ou un cycle de 4 à 7 chaînons substitué ;
X est -N(R10)-Y- ou -Y-N(R10)- ;
Y est C(O), SO2, un alkylène, un alkylène substitué, un alcénylène, un alcénylène substitué, un alcynylène,
ou un alcynylène substitué ;
R8 est H, un hétéroaryle, un hétéroaryle substitué, un phényl, ou un phényle substitué
par un halogène, un alkyle, un alcoxy, un haloalkyle, ou un haloalcoxy dans lequel
au moins l'un de R8 et R9 est un phényle substitué par un halogène, un alkyle, un haloalkyle, un alcoxy, et
un haloalcoxy à la position para ou méta ; ou dans lequel l'un de R8 et R9 est un phényle substitué par un halogène, un alkyle, un haloalkyle, un alcoxy, et
un haloalcoxy à la position para ou méta ; et l'autre de R8 et R9 est H, un halogène, OH, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, un C1-6 haloalcoxy ; ou dans lequel l'un de R8 et R9 est un phényle substitué par un halogène, un alkyle, un haloalkyle, un alcoxy, et
un haloalcoxy à la position para ou méta ; et l'autre de R8 et R9 est H ;
R10 est H, un C1-6 alkyle, ou un C1-6 alkyle substitué ;
R11 est H, un hétérocycloalkyle, un hétérocycloalkyle substitué, un aryle, un aryle substitué,
un hétéroaryle, ou un hétéroaryle substitué ; et
R12 est H, un alkyle, un alkyle substitué, un alcényle, un alcényle substitué, un alcynyle,
un alcynyle substitué ou NR3R4 ; dans lequel substitué fait référence à un groupe dans lequel un ou plusieurs atomes
d'hydrogène sont chacun indépendamment remplacés par un ou plusieurs substituants
identiques ou différents dans lequel les substituants incluent -X, -R33, -OH, =O, -OR33, SR33, -SH, =S, -NR33R34, =NR33, -CX3,-CF3, -CN, -NO2, -S(O)2R33, -OS(O2)OH, -OS(O)2R33, -OP(O)(OR33)(OR34), -C(O)R33,-C(S)R33, -C(O)OR39, -C(O)NR33R34, -C(O)OH, -C(S)OR33, -NR35C(O)NR33R34,-NR35C(S)NR33R34, -NR35C(NR33)NR33R34, -C(NR33)NR33R34, -S(O)2NR33R34,-NR35S(O)2R33, -NR35C(O)R33, et S(O)R33 où chaque X est indépendamment un halo ;
chaque R33 et R34 est indépendamment l'hydrogène, un alkyle, un alkyle substitué, un aryle, un aryle
substitué, un arylalkyle, un arylalkyle substitué, un cycloalkyle, un cycloalkyle
substitué, un hétérocycloalkyle, un hétérocycloalkyle substitué, un hétéroaryle, un
hétéroaryle substitué, un hétéroarylalkyle, un hétéroarylalkyle substitué, -NR35R36, -C(O)R35 ou -S(O)2R35 ou facultativement R33 et R34 avec l'atome auquel R33 et R34 sont attachés forment un ou plusieurs cycles hétérocycloalkyle, hétérocycloalkyle
substitués, hétéroaryle, ou hétéroaryle substitués ; et R35 et R36 sont indépendamment l'hydrogène, un alkyle, un alkyle substitué, un aryle, un aryle
substitué, un arylalkyle, un arylalkyle substitué, un cycloalkyle, un cycloalkyle
substitué, un hétérocycloalkyle, un hétérocycloalkyle substitué, un hétéroaryle, un
hétéroaryle substitué, un hétéroarylalkyle ou un hétéroarylalkyle substitué, ou facultativement
R35 et R36 avec l'atome d'azote auquel R35 et R36 sont attachés forment un ou plusieurs cycles hétérocycloalkyle, hétérocycloalkyle
substitués, hétéroaryle, ou hétéroaryle substitués.
2. Composé selon la revendication 1, dans lequel R1 est OH ou SH.
3. Composé selon la revendication 1, dans lequel R1 est OH.
4. Composé selon l'une quelconque des revendications 1 à 3, dans lequel R2 est H ou un C1-6 alkyle.
5. Composé selon l'une quelconque des revendications 1 à 3, dans lequel R2 est H.
6. Composé selon l'une quelconque des revendications 1 à 5, dans lequel R3 et R4 sont chacun indépendamment H, un C1-6 alkyle, ou un C1-6 haloalkyle.
7. Composé selon l'une quelconque des revendications 1 à 5, dans lequel R3 et R4 sont chacun indépendamment H ou un C1-6 alkyle.
8. Composé selon l'une quelconque des revendications 1 à 5, dans lequel R3 et R4 sont chacun H.
9. Composé selon l'une quelconque des revendications 1 à 8, dans lequel R5 est OH, SH, NH2, ou un C1-6 alcoxy.
10. Composé selon l'une quelconque des revendications 1 à 8, dans lequel R5 est OH.
11. Composé selon l'une quelconque des revendications 1 à 10, dans lequel au moins l'un
de R6 et R7 est un halo ou un groupe fonctionnel substitué par au moins un halo.
12. Composé selon l'une quelconque des revendications 1 à 10, dans lequel au moins l'un
de R6 et R7 est indépendamment un alcoxy ou un alcoxy substitué.
13. Composé selon l'une quelconque des revendications 1 à 10, dans lequel au moins l'un
de R6 et R7 est indépendamment un aryle, un aryle substitué, un hétéroaryle, un hétéroaryle substitué,
un hétérocycloalkyle, ou un hétérocycloalkyle substitué.
14. Composé selon l'une quelconque des revendications 1 à 13, dans lequel R8 est un phényle substitué ou un hétéroaryle substitué.
15. Composé selon l'une quelconque des revendications 1 à 13, dans lequel l'un de R8 et R9 est un phényle substitué, ou R8 est un pyridyle substitué.
16. Composé selon l'une quelconque des revendications 1 à 13, dans lequel l'un de R8 et R9 est un phényle ou un phényle substitué par un halogène, un alkyle, un haloalkyle,
un alcoxy, ou un haloalcoxy à la position para et/ou méta.
17. Composé selon l'une quelconque des revendications 1 à 13, dans lequel R8 est un pyridyle ou un pyridyle substitué par un halogène, un alkyle, un haloalkyle,
un alcoxy, ou un haloalcoxy à la position para et/ou méta.
18. Composé selon la revendication 1, dans lequel le composé est un composé de Formule
II :
dans laquelle :
R21 est H, un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ;
R22 est H, un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ;
Z1 est CR23 ; et R23 est H, un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ;
à la condition qu'au moins l'un de R21 et R22 et R23, s'ils sont présents, soit un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
19. Composé selon la revendication 18, dans lequel R21 est H, Cl, F, un méthyle, un éthyle, un trifluorométhyle, un méthoxy, un éthoxy,
ou un trifluorométhoxy.
20. Composé selon la revendication 18, dans lequel R22 est H, Cl, F, un méthyle, un éthyle, un trifluorométhyle, un méthoxy, un éthoxy,
ou un trifluorométhoxy.
21. Composé selon la revendication 18, dans lequel R23 est H, Cl, F, un méthyle, un éthyle, un trifluorométhyle, un méthoxy, un éthoxy,
ou un trifluorométhoxy.
22. Composé selon la revendication 18, dans lequel l'un de R21, R22, et R23 est un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ; et les deux autres de R21, R22, et R23 sont chacun H.
23. Composé selon la revendication 18, dans lequel l'un de R21 et R23 est un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ; et l'autre de R21 et R23 est H.
24. Composé selon la revendication 23, dans lequel R22 est H.
25. Composé selon la revendication 18, dans lequel deux de R21, R22, et R23 sont chacun indépendamment un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ; et l'autre de R21, R22, et R23 est H.
26. Composé selon la revendication 25, dans lequel R22 est H.
27. Composé selon la revendication 18, dans lequel R21, R22, et R23 sont chacun indépendamment un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
28. Composé selon la revendication 18, dans lequel l'un de R21 et R22 est un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ; et l'autre de R21 et R22 est H.
29. Composé selon la revendication 18, dans lequel le composé est de Formule IIa :
dans laquelle :
R21 est H, un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ; et
R22 est H, un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ;
à la condition qu'au moins l'un de R21 et R22 soit un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
30. Composé selon la revendication 29, dans lequel R21 est H ; et R22 est un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
31. Composé selon la revendication 29, dans lequel R21 est H ; et R22 est un C1-6 alkyle ou un C1-6 haloalkyle.
32. Composé selon la revendication 31, dans lequel R22 est le méthyle ou un C1-2 haloalkyle.
33. Composé selon la revendication 31, dans lequel R22 est le méthyle ou l'éthyle.
34. Composé selon la revendication 29, dans lequel R22 est H ; et R21 est un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
35. Composé selon la revendication 29, dans lequel R22 est H ; et R21 est un C1-6 alkyle ou un C1-6 haloalkyle.
36. Composé selon la revendication 35, dans lequel R21 est le méthyle ou un C1-2 haloalkyle.
37. Composé selon la revendication 35, dans lequel R21 est le méthyle ou l'éthyle.
38. Composé selon la revendication 29, dans lequel R21 et R22 sont chacun indépendamment un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
39. Composé selon la revendication 29, dans lequel R21 et R22 sont chacun indépendamment un C1-2 alkyle ou un C1-2 haloalkyle.
40. Composé selon la revendication 1, dans lequel le composé est de Formule III :
dans laquelle :
R24 est H, un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ;
R25 est H, un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ;
Z2 est N ou CR26 ; et R26 est H, un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ;
à la condition qu'au moins l'un de R24 et R25 et R26, s'ils sont présents, soit un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
41. Composé selon la revendication 40, dans lequel Z2 est CR26.
42. Composé selon la revendication 40 ou 41, dans lequel R24 est H, Cl, F, le méthyle, l'éthyle, le trifluorométhyle, un méthoxy, un éthoxy, ou
un trifluorométhoxy.
43. Composé selon l'une quelconque des revendications 40 à 42, dans lequel R25 est H, Cl, F, le méthyle, l'éthyle, le trifluorométhyle, un méthoxy, un éthoxy, ou
un trifluorométhoxy.
44. Composé selon l'une quelconque des revendications 40 à 43, dans lequel Z2 est CR26 ; R26 est H, Cl, F, le méthyle, l'éthyle, le trifluorométhyle, un méthoxy, un éthoxy, ou
un trifluorométhoxy.
45. Composé selon la revendication 40, dans lequel Z2 est CR26 ; l'un de R24, R25, et R26 est un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ; et les deux autres de R24, R25, et R26 sont chacun H.
46. Composé selon la revendication 40, dans lequel Z2 est CR26 ; l'un de R24 et R26 est un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ; et l'autre de R24 et R26 est H.
47. Composé selon la revendication 40, dans lequel Z2 est CR26 ; deux de R24, R25, et R26 sont chacun indépendamment un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ; et l'autre de R24, R25, et R26 est H.
48. Composé selon la revendication 40, dans lequel Z2 est CR26 ; R24, R25, et R26 sont chacun indépendamment un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
49. Composé selon la revendication 40, dans lequel Z2 est N.
50. Composé selon la revendication 49, dans lequel l'un de R24 et R25 est un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ; et l'autre de R24 et R25 est H.
51. Composé selon la revendication 40, dans lequel le composé est de Formule IIIa :
dans laquelle :
R24 est H, un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ; et
R25 est H, un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy ;
à la condition qu'au moins l'un de R24 et R25 soit un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
52. Composé selon la revendication 51, dans lequel R24 est H ; et R25 est un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
53. Composé selon la revendication 52, dans lequel R25 est le méthyle ou un C1-2 haloalkyle.
54. Composé selon la revendication 51, dans lequel R25 est H ; et R24 est un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
55. Composé selon la revendication 54, dans lequel R24 est le méthyle ou un C1-2 haloalkyle.
56. Composé selon la revendication 51, dans lequel R24 et R25 sont chacun indépendamment un halogène, un C1-6 alkyle, un C1-6 haloalkyle, un C1-6 alcoxy, ou un C1-6 haloalcoxy.
57. Composé selon la revendication 1, dans lequel le composé est :
l'acide 2-(4-hydroxy-2-oxo-7-phényl-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(7-(2-chlorophényl)-4-hydroxy-2-oxo-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(7-(3-chlorophényl)-4-hydroxy-2-oxo-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(7-(4- chlorophényl)-4-hydroxy-2-oxo-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-7-(3-(trifluorométhyl)phényl)-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-7-(4-(trifluorométhyl)phényl)-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-7-(3-(trifluorométhoxy)phényl)-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-7-(4-(trifluorométhoxy)phényl)-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(7-(3,4-dichlorophényl)-4-hydroxy-2-oxo-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(7-(3,4-difluorophényl)-4-hydroxy-2-oxo-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-7-(3,4,5-trifluorophényl)-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-7-(3-méthoxyphényl)-2-oxo-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-7-(4-méthoxyphényl)-2-oxo-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-7m-tolyl-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(4-hydroxy-2-oxo-7-p-tolyl-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(8-(2-chlorophényl)-4-hydroxy-2-oxo-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(8-(3-chlorophényl)-4-hydroxy-2-oxo-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(8-(4-chlorophényl)-4-hydroxy-2-oxo-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(4-hydroxy-2-oxo-8-(3-(trifluorométhyl)phényl)-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-8-(4-(trifluorométhyl)phényl)-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-8-(3-(trifluorométhoxy)phényl)-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-8-(4-(trifluorométhoxy)phényl)-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(8-(3,4-dichlorophényl)-4-hydroxy-2-oxo-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(8-(3,4-difluorophényl)-4-hydroxy-2-oxo-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-8-(3,4,5-trifluorophényl)-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-8-(3-méthoxyphényl)-2-oxo-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-8-(4-méthoxyphényl)-2-oxo-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-8-m-tolyl-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(4-hydroxy-2-oxo-8-p-tolyl-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(4-hydroxy-7-(6-méthoxypyridin-3-yl)-2-oxo-2H-chromène-3-carboxamido)acétique
;
l'acide 2-(4-hydroxy-2-oxo-7-(pyridin-4-yl)-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(4-hydroxy-2-oxo-7-(pyridin-3-yl)-2H-chromène-3-carboxamido)acétique ;
l'acide 2-(4-hydroxy-8-(3-trifluorométhyl)phényl-2H-chromène-3-carboxamido)acétique.
58. Composition pharmaceutique comprenant un excipient, un adjuvant ou un support pharmaceutiquement
acceptable, et une quantité thérapeutiquement efficace d'un composé selon l'une quelconque
des revendications 1 à 57.
59. Composition pharmaceutique selon la revendication 58, comprenant en outre un agent
stimulant l'érythropoïèse ou un agent chimiothérapeutique.
60. Composition pharmaceutique selon la revendication 58, dans laquelle le composé selon
l'une quelconque des revendications 1 à 57 est présent dans une quantité efficace
pour le traitement de l'ischémie, l'anémie, la cicatrisation, l'autogreffe, l'allogreffe,
la xénogreffe, l'hypertension artérielle systémique, la thalassémie, le diabète, le
cancer, un trouble inflammatoire, ou une combinaison de ceux-ci.
61. Composition pharmaceutique selon la revendication 58, dans laquelle le composé selon
l'une quelconque des revendications 1 à 57 est présent dans une quantité efficace
pour le traitement d'une maladie, d'un trouble, ou d'une pathologie associés au taux
de HIF ou à l'activité de HIF qui est l'ischémie, l'anémie, la cicatrisation, l'autogreffe,
l'allogreffe, la xénogreffe, l'hypertension artérielle systémique, la thalassémie,
le diabète, le cancer, un trouble inflammatoire, ou une combinaison de ceux-ci.
62. Utilisation d'un composé selon l'une quelconque des revendications 1 à 57 dans la
fabrication d'un médicament pour le traitement d'une maladie, d'un trouble, ou d'une
pathologie qui est l'ischémie, l'anémie, la cicatrisation, l'autogreffe, l'allogreffe,
la xénogreffe, l'hypertension artérielle systémique, la thalassémie, le diabète, le
cancer, un trouble inflammatoire, ou une combinaison de ceux-ci.